Review: Skin and the Immune System
Journal of Clinical & Experimental Dermatology Research

Journal of Clinical & Experimental Dermatology Research
Open Access

ISSN: 2155-9554

+44 1478 350008

Review Article - (2012) Volume 0, Issue 0

Review: Skin and the Immune System

Elizabeth R. Mann1, Kathryn M. Smith2, David Bernardo1, Hafid Omar Al-Hassi1, Stella C. Knight1* and Ailsa L. Hart1,3
1Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark’s Campus, Harrow, HA1 3UJ, UK
2School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington Campus, Leicestershire, LE12 5RD, UK
3St.Mark’s Hospital, North West London Hospitals NHS Trust, Harrow, HA1 3UJ, UK
*Corresponding Author: Stella C. Knight, Antigen Presentation Research Group, Imperial College London, Northwick Park and St. Mark’s Hospital Watford Road, Harrow, HA1 3UJ, UK, Tel: +44 (0) 20 8869 3532, Fax: +44 (0) 20 8869 3532 Email:


The skin immune system comprises a complex network of cells, functioning both in immunity against invading pathogens but also tolerogenic mechanisms to ensure maintenance of immune homeostasis. The nature of antigens present and interplay between the cutaneous innate and adaptive immune systems determine the type of immune response generated. Dendritic cells are the key players in bridging innate and adaptive immune responses due to their inherent plasticity, direct roles in both type of immune responses, and cross-talk with other immune cells. This review dissects the functional roles of components of both innate and adaptive immune systems in the skin, with a special focus on cutaneous dendritic cells as the only cells capable of inducing primary immune responses, their ability
to generate either immunogenic or tolerogenic immune responses, and ability to direct effector cells back to the skin via imprinting of skin-homing properties on T-cells. Finally the reciprocal interactions between the skin microbiota and immune system and their role in host defence and disease have been discussed.



The skin is the largest organ in the body. Its primary function is to serve as a barrier protecting the internal organs from physical and chemical attack, invasion of pathogens and excessive water loss. As the primary immunological barrier to the external environment, the skin is rich in immune cells, forming a complex network called the “skin immune system” [1] comprising both innate and adaptive immune cells [2]. The skin is colonized by a diverse milieu of microorganisms [3,4]; reciprocal interactions between the skin microbiota and immune system play a role in determining the nature of immune responses generated in the skin [5-8]. This review highlights recent insights into cells of the skin immune system and interplay between the skin microbiome, the immune system, and cutaneous inflammatory disease.

The Innate Immune System

The skin has constitutive innate immune mechanisms that help to protect against pathogens. The uppermost layer of the epidermis, the corneal layer, is a unique layer not present in other epithelia exposed to the external environment (such as the gut and lung epithelia) [2,9]. The corneal layer is comprised of dead keratinocytes that provide a physical barrier to the skin [2,9]. Keratinocytes produce antimicrobial peptides (AMPs) in response to infection, including human β-defensins, cathelicidins and RNases [10,11], which can be found in the corneal layer.

Beneath the corneal layer of the epidermis are the granular, spinous and basal layers. These layers consist of keratinocytes expressing pattern recognition receptors (PRRs) which can detect invading microorganisms via pathogen-associated molecular patterns (PAMPs) expressed on the invading microorganism cell surface; this interaction initiates early immune responses in the skin [12]. Dendritic cells (DC) of the epidermis, known as Langerhans’ cells (LC) also express PRRs to initiate early immune responses. The underlying dermis is anatomically more complicated, with greater cell diversity. Immune cells present in the dermis also express PRRs for detection of invading pathogens and include DC, macrophages, mast cells, B and T-cells, plasma cells, natural killer (NK) cells, fibroblasts and innate lymphocytes γδ T-cells and invariant natural killer T-cells (iNKTcells) [2,9]. Although a crucial function of these cells is detection of invading microorganisms via PRRs, another important function is to maintain the balance between the host and the skin microbiome. It has been hypothesised that, perhaps like commensal microbes found in the gastro-intestinal (GI) tract, these skin microbes have a beneficial role in preventing pathogenic microbes from occupying these unique microenvironments [8].

Interaction of innate immune cells or their products influences their function. However for the purpose of this review, for this section we will focus on the functional roles of innate immune cells and their interactions with DC specifically. Although DC have specific innate properties, they are unique in their potency at generating T-cell mediated immune responses and can therefore be thought of as a link between the innate and the adaptive immune systems.

Dendritic cells

Dendritic cells (DC) are professional antigen-presenting cells, and the main gate-keepers of the immune system. However, in this section we will focus on the innate properties of DC only (see section 3 for adaptive properties of skin DC). DC are mononuclear phagocytes, and act as immune sentinels, patrolling the peripheral tissues for antigens. DC recognize antigen via a diverse array of PRRs that can sense PAMPs on invading pathogens [13,14]. These PRRs recognize a wide range of PAMPs which leads to DC activation [14-16].

In addition to recognizing a wide range of microbial products, innate DC receptors also recognize so-called endogenous ligands from host cellular debris, in particular from injured or dying tissue, termed DAMPs (damage-associated molecular patterns) [17-19]. Therefore, as well as recognizing invading pathogens, DC can also recognize a wide range of self-antigens that are released during tissue damage, inflammation, or necrosis, leading to inappropriate activation resulting in sterile inflammation or autoimmune responses [17-20].

DC recognise whether to initiate an immunogenic immune response (to pathogenic antigens) or tolerogenic immune response (to self antigen or commensal microbiota) via antigen recognition involving PAMP recognitions by PRRs and presence of cytokines or other inflammatory/non-inflammatory mediators. There are three subsets of human skin DC in the steady state; Langerhans’ cells (LC), dermal DC (dDC) and plasmacytoid DC (pDC) [21].

Langerhans’ cells: LC are interspersed throughout the epidermis, where they mediate immune surveillance of substances in the external environment that come into contact with the skin. LC are a unique subset of DC, originally identified by their characteristic organelle, the Birbeck granule. The function of the Birbeck granule is unclear, but is likely to include receptor-mediated endocytosis and transport of cellular materials into the extracellular space [22]. LC are now defined by their location in the epidermis, combined with expression of CD207 (langerin) and CD1a [23]. Langerin is a membrane-bound C-type lectin receptor (CLR) [24] that recognises mannosylated ligands (PAMPs) on the surface of a wide range of pathogens, including viruses, bacteria, fungi and protozoa [25]. Upon antigen encounter, receptor-mediated endocytosis by the LC occurs, followed by trafficking of CD1a and langerin to the Birbeck granule where they play a role in antigen processing [26].

Due to their location in the epidermis, LC are in intimate contact with keratinocytes, and are the first DC to come into contact with microbial antigens in the skin. Studies of skin biopsies from atopic dermatitis (AD) patients have demonstrated the presence of DC expressing the high affinity surface receptor for IgE (FcεRI). Engagement of FcεRI on LC promotes the release of chemokines CCL2, CCL17 and CCL22, attracting cells expressing chemokine receptors, and perhaps enhancing allergen presentation to T-cells and supporting Th2 differentiation [27]. However, LC have also been implicated in immune tolerance in the skin. This is partly due to the expression of surface molecules involved in inhibition of T-cell responses such as inducible co-stimulatory molecule ligand ICOS-L or the production of immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) [28]. There is still significant debate regarding the functional role of LC in humans which will be discussed in further detail in section 3.2.

Dermal dendritic cells (dDC): myeloid: Dermal DC (dDC) are considered analogous to interstitial DC found in connective tissue and the stroma of other organs [29-31]. Various DC subsets reside in the dermis in humans; CD1c (BDCA-1) is often used to describe dermis based myeloid DC (mDC) [29,30,32]. dDC can exist in an immature state with cytoplasmic ruffles and express various PRRs [33]. More mature dDC (post-antigen stimulation) have cytoplasmic veils and express higher levels of co-stimulatory molecules such as CD83, and lower levels of PRRs [34] (limiting their involvement in innate immune responses).

Mature dermal mDC rapidly migrate to the skin-draining lymph nodes, to prime T-cell responses [35,36], but activated dDC also participate in the innate immune response by secretion of cytokines and chemokines [37]. Chemokine and cytokine production can be beneficial when responding towards invading pathogens, but can also underlie persistent inflammation in chronic inflammatory disease. Tumour necrosis factor (TNF) and inducible nitric oxide synthase (iNOS) are produced by a subset of dDC called TIP-DC (TNF and iNOS-producing DC) [38,39], and exhibit pro-inflammatory effects in psoriasis [39].

Dermal dendritic cells: plasmacytoid: Plasmacytoid DC (pDC) are rare in human skin, but are mainly found in the dermis. pDC express CD123 and BDCA-2, and are CD11c- [40]. They are mainly characterised by their ability to produce large amounts of type 1 IFN during viral infections, 10,000x more than any other cell type [40,41]. Early activation of pDC triggers an innate immune response via crosstalk with keratinocytes (discussed in more detail in section 2.2) leading to ligation of TLR9 on pDC with resulting IFN-α production [42]. This pathway has been implicated in the pathogenesis of systemic lupus erythematosus and psoriasis [43,44].


Epidermal keratinocytes are pro-inflammatory effector cells strategically positioned at the outermost layer of the body to respond to invading pathogens by coordinated production of anti-microbial peptides (AMPs), proinflammatory cytokines and chemokines. Keratinocytes in the skin are an important source of β-defensins and cathelicidins; local production of AMPs during skin infections can be increased by T-cell derived cytokines, in particular IL-17A and IL-22, which are produced by Th17 cells [45]. Keratinocytes express several PRRs including TLRs [46,47]. TLR expression by keratinocytes may be crucial for promoting skin immune responses; strong TLR activation of keratinocytes leads to polarisation of Th1 responses and production of inflammatory type I interferons (IFNs) [48].

AMPs are expressed at high levels in the skin of psoriasis patients, and thought to be responsible for lack of skin infections in these patients [49]. Keratinocytes can also contribute to loss of immune tolerance to self-antigens in psoriasis patients via production of a cathelicidin AMP called LL37 [42]. In addition to AMPs, keratinocytes constitutively produce numerous cytokines [50] including IL-1, which has a broad range of biological effects [51]. A role for IL-1α in skin disease was suggested by a transgenic mouse model [52], with overexpression of IL-1F6 by keratinocytes leading to skin inflammation [53]. Expression of IL-1F6 was also increased in psoriatic epithelium. Other studies have shown epidermal keratinocytes can instigate cutaneous inflammation [54-57] and that dysregulation of keratinocyte function can trigger systemic autoimmune responses by lymphocytes [58,59].

Keratinocytes also express chemokines and can therefore modulate immune responses by attracting different cell types into the skin e.g. recruitment of effector T-cells during disease characterised by T-cell infiltration such as psoriasis and T-cell lymphoma [50]. Keratinocytes can also recruit neutrophils to the inflamed epidermis, but this property will be discussed in further detail in section 2.2.

Keratinocyte: DC crosstalk: Keratinocytes of the skin produce cytokines including IL-1 which has a broad range of biological effects, including DC activation [51]. Keratinocytes may also condition DC to promote a dysregulated immune response, for example, through secretion of thymic stromal lymphopoietin (TSL) in allergic inflammation [60]. Another important function of keratinocytes is their role in the activation and migration of Langerhans’ cells (LC). Keratinocytes constitutively express TGFβ, a cytokine indispensable for immigration of LC precursors in the epidermis; the epidermis of TGFβ knockout mice does not contain LC [61]. Immigration of LC precursors into the epidermis induces keratinocytes to secrete MCP-1/CCL2, which constitutively recruits LC (and other DC) to the skin [62]. MCP-1/CCL2 production is increased in psoriatic skin [9]. Acute upregulation of retinoic acid early transcript 1 (RAE1), expressed on keratinocytes in the skin, leads to inflammation involving redistribution of LC (and γδ T-cells) within the epidermal compartment (via interaction with RAE1 receptor natural killer group 2, member D known as NKG2D on LC), followed by an influx of innate αβ T-cells [63].

Keratinocytes also interact with pDC in the skin; early activation of pDC triggers increased expression of AMP LL37 (cathelicidin) by keratinocytes [64]. Cathelicidin LL37 bound to self-DNA fragments are released from dead/dying keratinocytes and in turn trigger TLR9 activation in pDC, resulting in IFN-α production and activation of adaptive immune responses [42]. Studies have raised the possibility that high levels of cathelicidins expressed by keratinocytes in psoriatic skin can break tolerance to self DNA, leading to sustained activation of pDC and type I IFN production [42].


Neutrophils express a variety of PRRs and are a key component of innate immunity and are essential for protection from bacterial infections due to their ability to recognize, phagocytose and ultimately destroy pathogenic organisms [65-68]. The protective role of neutrophils is associated with rapid recruitment to sites of tissue damage and pathogen entry; neutrophil recruitment from the circulation to the skin is mediated by multiple factors, including proinflammatory cytokines such as IL-1α, IL-1β, tumour necrosis factor (TNF) and IL-6, and chemokines. Chemokines produced by activated keratinocytes recruit neutrophils to inflamed areas of the skin (e.g. the inflamed epidermis in patients with psoriasis [50]. Adhesion molecules are also required for neutrophil recruitment to the skin; these molecules promote neutrophil rolling, adhesion and diapedesis [69]. Chemokines and adhesion molecules involved in neutrophil recruitment to the skin are summarised in Table 1.

Innate cell PRRs/activating receptors Products/molecules Innate function
DC (general) TLRs, CLRs, RLRs, NLRs Various Immune sentinels; proinflammatory or anti-inflammatory effects
LC Langerin/CD207 (CLR) FcγR and FcεR DEC205 Chemokines CCL2, CCL17 and CCL22 Attraction of other leukocytes to sites of inflammation
Surface molecules ICOS-L Inhibition of T-cell responses (immune tolerance)
Enzyme IDO Immunoregulatory activity
dDC (mDC) TLR2, TLR4, CD206, DC-SIGN (CD209) CCL17, CCL22 Attraction of other leukocytes to sites of inflammation
TNF and iNOS Proinflammatory effects
dDC (pDC) TLR7, TLR9 Type 1 IFNs Immunity against viral infections and promote function of T-cells, B-cells, NK cells
Keratinocyte TLR1, TLR2, TLR4, TLR5, TLR6 (cell surface) and TLR3, TLR9 (endosomes) AMPs: β-defensins and cathelicidin Anti-microbial defence
AMP: LL37 Loss of immune tolerance
IL-1, IL-6, IL-10, TNF, TGFβ Broad range of effects
CXCL1, CXCL8 Mediate attraction of neutrophils and other immune cells to inflamed skin via CXCR2 expression
Neutrophil TLRs (excluding TLR3 and TLR7) IL-1α, IL-1β, TNF, IL-6 Host defence
Chemokine CXCR2 Migration towards CXCL1- and CXCL8-expressing keratinocytes in inflamed skin
Adhesion molecules L-selectinand LFA-1 (αLβ2) Promote neutrophil rolling, adhesion and diapedesis for recruitment to skin
AMPs: cathelicidins, lysozyme, α-defensins Direct microbicidal activity
Proteinases: cathepsin G, neutrphil elastase and proteinase 3/myeloblastin Contain acid hydrolases to degrade bacterial components
Proteins: lactoferrin, transcobalamin II, NGAL and calpotectin Sequester essential nutrients to limit bacterial growth
Classically activated macrophage TLRs (T-cell/NK cell-derived IFNγ and macrophage-derived TNF needed in combination with TLR ligation for macrophage activation) IL-12 Induces IFNγ production from T-cells and NK cells
TNF Activates macrophage (second signal)
IL-23 Promotes inflammatory immune responses
Toxic intermediates (NO and ROI) Bactericidal activity
Alternatively activated macrophage TLRs (CD40/CD44 signalling can occur instead of TLR ligation). FcγR ligation by IC required in combination with TLR ligation for activation IL-10/no IL-12/no toxic intermediates Potent anti-inflammatory effects
G-CSF Anti-inflammatory effects via DC modulation
Fibronectin, βIG-H3 Fibrogenesispromoting tissue repair and collagen formation
Arginine Polyamine and proline synthesis promoting cell growth and tissue repair
Mast cell TLRs (murine skin MC express TLR3, TLR7, TLR9) TNFα, IL-1, IL-6, IL-10, lipid mediators (PG and LT) Contribute to allergic and inflammatory responses
Chemokines Recruitment to skin
NK cell NKG2A, NKG2D (stressed/dying cells) TLR3, TLR9 (exogenous microbes) IFNγ, TNFα Cytotoxicity and inflammation
IL-22 (in response to IL-23) AMP production, host defence, constraint of inflammation
IL-17 (in response to zymosan) AMP production and host defence
Chemokines CXCR3, CCR5 and CCR6 Migration towards CXCL10, CCL5 and CCL20 on keratinocytes of inflamed skin
NKT cell Invariant TCRα chain combined with limited set of TCRβ chains IFNγ, IL-4, IL-2, IL-5, IL-10, IL-13, TNFα Inflammatory and allergic responses
Perforin, granzymes, FasL, TRAIL, granulysin Cytotoxicity
γδ T-cell TLRs(microbial recognition) Vδ1 receptor (stressed/dying cells and tumour cells) NKG2D (stressed/dying cells and tumour cells) IL-2, IFNγ, TNFα Inflammation
CCL3, CCL4, CCL5, XCL1 Chemotaxis to recruit cells to site of damage
KGF Tissue repair/wound healing
IGF-1, IL-2 Epidermal maintenance and development
IL-17 Host defence

Table 1: Innate immune cells of the skin.

Once neutrophils encounter pathogens in the skin, they use multiple mechanisms to facilitate bacterial killing, including phagocytosis to engulf the bacteria and oxidative burst to generate reactive oxygen species that mediate bacterial killing. They also produce AMPs (such as cathelicidins, lysozyme and α-defensins) that have direct microbicidal activity, and proteinases (such as cathepsin G, neutrophil elastase and proteinase 3/myeloblastin) with acid hydrolases that degrade bacterial components. Neutrophils also express proteins that sequester essential nutrients to limit bacterial growth, including lactoferrin, transcobalamin II, neutrophil gelatinase-associated lipocalin (NGAL) and calpotectin [66,70,71]. Subsequent clearance of recruited neutrophils is then carried out by macrophage/monocyte populations.

A hallmark of Staphylococcus aureus infections in the skin is neutrophil abscess formation, which is required for bacterial clearance [72]. Impaired neutrophil function in humans leads to uncontrolled dermal infections caused by group A Streptococcus or Staphylococcus aureus [73-75], highlighting the importance of neutrophils for immunity in the skin.

Neutrophil: DC crosstalk: Neutrophils can induce maturation of DC through contact-dependent interactions involving CD18 and CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1) on neutrophils [76-78] and DC-SIGN (DC-specific ICAM3- grabbing non integrin) on DC [77,78]. Neutrophil-matured DC acquire potential to induce T-cell proliferation and polarization towards Th1 responses [76,78], implicating a role for neutrophil: DC crosstalk in inflammatory skin disorders with increased DC-SIGN expression on skin DC, such as psoriasis [79].


Macrophages are mononuclear phagocytes and are also deemed professional antigen-presenting cells due to their ability to present antigen to T-cells; however, macrophages do not possess the potency of DC to initiate primary immune responses [80-82]. The innate functions of macrophages play a crucial role in human host defence via phagocytosis and clearance of infectious agents by secretion of cytokines and chemokines. Resident macrophages in the skin maintain tissue homeostasis and dampen initiation of inflammation by clearance of allergens, whilst bone marrow-derived monocytes leave the circulation and migrate towards sites of inflammation in the skin where they differentiate into mature macrophages [83].

Classically activated macrophages: The biological functions of activated macrophages involve migration to sites of inflammation to encounter pathogens and degrade them; activated macrophages display no enhanced phagocytosis compared to resting cells [84] but they do possess a markedly enhanced ability to kill and degrade intracellular microorganisms via production of toxic intermediates (nitric oxide NO and reactive oxygen intermediates ROI). Macrophages are activated through ligation of PRRs such as TLRs via microbial PAMPs [85,86]; in the classically activated macrophage this involves production of proinflammatory cytokines that induce inflammatory cytokine production by T-cells (Table 1) which in turn acts on the macrophage to enhance cytokine secretion, antigen-presentation and bactericidal activity [87,88]. Such cytokine activity is critical for establishment of effective host defence against intracellular pathogens [89]. Classical macrophage activation is characterized by a heightened ability to produce IL-12 and IL-23 [90] and toxic intermediates; these cells are commonly referred to as M1 macrophages (mirroring Th1 nomenclature) [91].

Classically activated macrophages in the dermis display enhanced production of inflammatory cytokines IL-12 and IL-23 in psoriasis (Fuentes- Duculan J; Zaba LC J Invest Dermatol 2010), likely to contribute to the pathogenic inflammation in this disease. However, the pro-inflammatory properties of classically activated macrophages are useful in wound healing; during the short inflammatory stage, classically activated macrophages exert functions like antigenpresentation, phagocytosis and production of inflammatory cytokines and growth factors that facilitate the wound healing process [92].

Alternatively activated macrophages: Th2 cytokines IL-4 and IL-13 induce a distinct activation program in macrophages, referred to as “alternately activated macrophages” [93,94]. Alternatively activated macrophages are sometimes referred to as “type II activated macrophages” due to their ability to preferentially induce Th2 responses [95], and are generated upon exposure to two signals; a macrophage stimulatory signal which may include TLR signalling or signalling via CD40 or CD44, and FcγR ligation by immune complexes (IC) [95,96]. Alternatively activated macrophages exert potent anti-inflammatory effects due to their production of IL-10 [96] and lack of IL-12 production [97]; they have a suppressive effect on T-cell proliferation [98] and inflammatory responses [99]. These cells fail to make toxic intermediates [100] and are therefore compromised in their ability to kill intracellular microbes.

Recent studies on alternatively activated macrophages have focused on their potential to mediate wound-healing, angiogenesis and ECM deposition; these cells produce high levels of fibronectin and matrix-associated protein βIG-H3 [101], promote fibrogenesis from fibroblastoid cells [102] and induction of arginine in these cells may lead to polyamine and proline biosynthesis, promoting cell growth, collagen formation and tissue repair [103]. However, alternatively activated

Granulocyte colony stimulating factor (G-CSF) is produced by macrophages under certain conditions e.g. conditioning with probiotic bacteria [106]; G-CSF elicits anti-inflammatory effects mediated through modulation of DC [107], highlighting the relevance of the skin microbiome in maintaining the balance between immunity and immune tolerance in the skin (discussed in section 4). Reciprocally, DC-produced cytokines can affect the function of macrophages e.g. DC production of IL-15 (in response to IFN-α) controls the responsiveness of macrophages to TLR4 ligands [108] suggesting a role for crosstalk between skin macrophages and DC in bacterial skin infections and/or response to commensal bacteria.

Mast cells

Mast cells (MC) are innate immune cells involved in clearing bacterial [109-113] and parasitic [114-117] infections but are also thought to contribute to allergic and inflammatory responses via release of cytokines, chemokines, lipid mediators, proteases and biogenic amines upon cross-linking of cell-bound IgE by allergens. MC originate from bone marrow stem cells [118-120] and circulate as immature MC progenitor cells, completing their maturation upon recruitment into the peripheral tissues [121,122] e.g. the skin.

Human MC can be categorized into two different subtypes depending on the presence of different protease granules [123,124]. Cells containing tryptase alone are called MCT, whereas MC with only chymase are called MCC; MC with both tryptase and chymase are called MCTC, and it is this subset that is present in large amounts in the skin [125-127]. MC express different types of TLRs depending on the type and location of the MC; MC in murine skin specifically express TLRs 3,7 and 9 and upon stimulation via these TLRs, produce inflammatory mediators TNF-α and IL-6, amongst others [128].

Mast cell: DC crosstalk: MC have a direct effect on other immune cells such as DC; MC or MC products can induce cutaneous DC maturation and migration [129-131]. However, the action of MC on DC in the onset of inflammation is dependent on the context, as prostaglandin (PG) is produced by MC in response to allergens [132] which inhibits LC (epidermal DC) migration [133]. The functional role of MC in inflammatory responses such as contact hypersensitivity (CHS) in the skin is unclear; murine studies of MC in CHS have provided conflicting results with MC-deficient mice showing attenuated CHS responses in one study but not in another [134]. However more recent studies have demonstrated that activated DC induces MC activation, which in turn triggers migration and maturation of DC via cell-cell contact. This DC-MC interaction plays an essential role in the sensitization phase of CHS [135].

MC crosstalk with DC also plays an important role in regulation of protective adaptive immune responses against pathogens in the skin; recent murine studies have shown MC directly induce DC maturation resulting in a release of Th1 and Th17 polarising cytokines and such MC-primed DC stimulated efficient CD4+ Th1 and Th17 responses. Enhanced disease progression of MC-deficient mice in Leishmania major infection in the skin correlated with impaired induction of both Th1 and Th17 cells [136].

Innate immune lymphocytes

There are several lymphocyte classes that participate in innate immune responses in the skin; these include natural killer (NK) cells, natural killer T-cells (NKT-cells), invariant NKT-cells (iNKT-cells) and γδ T-cells.

Natural killer cells: Natural killer (NK) cells are able to kill cells that are virally infected, as well as cancer cells; however, they also produce a range of cytokines [137]. In humans, NK cells are defined as CD3-CD56+ or CD3-CD16+ lymphocytes. NK cells express several TLRs [138]; ligation by TLR ligands induces IFN-γ production and enhances cytotoxicity. However activating NK receptors also include those recognizing stress-induced self ligands e.g. NK cell receptor NKG2D recognizes human ULBP and MIC molecules expressed on stressed or dying cells [139,140]. Although the primary function of NK cells is cytotoxicity towards virally infected cells and cancer cells, NK cells have become increasingly recognized as contributors to pathophysiological situations such as psoriasis and AD. NK cells are recruited to the skin in inflammatory conditions via expression of chemokine receptors corresponding to ligands (chemoattractants) expressed on cutaneous keratinocytes (Table 1) [141,142].

Two distinct NK cell populations exist in the human skin which have the capacity to produce either IL-22 or both IL-22 and IL-17; these cutaneous NK cells are therefore likely to play a role in skin-mediated inflammatory diseases mediated by these cytokines, including atopic dermatitis (AD) and psoriasis. Both IL-17 and IL-22 induce synthesis of AMPs including cathelicidins and β-defensins from keratinocytes, demonstrating their participation in the host innate immune defence in the skin [143-147].

IL-23, produced by activated DC and macrophages [148], is crucial in stimulating IL-22 production by NK cells (NK-22 cells). Keratinocytes can also produce IL-23 and expression of IL-23 is enhanced in keratinocytes of psoriatic patients [149]. NK-22 cells have a diminished capacity to degranulate and produce IFN-γ [150,151]; but although IL-22 is necessary for production of antimicrobial molecules in the skin [152], an excessive IL-22 response may contribute to disease pathogenesis in psoriasis [146,153,154].

The other subset of NK cells in human skin are referred to as human lymphoid tissue inducer-like cells (LTi-like cells). LTi-like cells are able to produce both IL-17 and IL-22 [143,155] and the yeast wall product zymosan can elicit Il-17 production by these cells in vivo [156]. It is likely that these cells contribute to host defence but the production of IL-17 also implicates LTi-like cells in autoimmunity and inflammation. However, data on Lti-like cells in the skin is currently scarce.

NK cell: DC crosstalk: DC can efficiently enhance activation marker expression, proliferation, inflammatory cytokine production, and cytotoxic activity of NK cells, via the action of inflammatory mediators such as IL-12, TNFα and type 1 IFNs [157]. Reciprocally, NK cells promote DC maturation and increase their capacity to produce IL-12 and polarize Th1 responses [158]. NK-mediated effects on DC are dependent on TNFα and IFNγ. A direct contact between DC and NK cells was first demonstrated in skin lesions resulting from fungal (Malassezia) infections of the skin and was later highlighted in specific forms of induced dermatitis [159]. It has been hypothesised that dysregulation of LC: NK cell crosstalk may participate in the chronic inflammation observed in malignant Langerhans histiocytosis [160]. The reciprocal activating interaction between DC and NK cells may also play a pivotal role in immune defense against viral infections (and tumours).

Natural killer T-cells: Natural killer T-cells (NKT-cells) coexpress T-cell receptor (TCR) and NK lineage markers such as CD16, CD56, CD57, CD94 and CD161, and unlike conventional T-cells, recognize glycolipid antigens in the context of MHC class I-like antigenpresenting molecule CD1d. The most widely studied NKT-cells are type 1, or classical NKT-cells (also known as invariant NKT-cells; iNKT cells), characterized by their ability to recognise the prototypic CD1d-restricted glycosphingolipid antigen α-GalCer (a marine sponge-derived compound with potent immunoregulatory potential). iNKT-cells have a highly restricted TCR repertoire as they express an invariant Vα24-Jα18 rearranged TCR-α chain, typically coexpressed with Vβ11-containing β chain [161-163]. Type II nonclassical NKTcells express diverse TCR-α chains, are generally not reactive with αGalCer but are also specific for antigens presented by CD1d [164].

NKT-cells only constitute a small proportion of lymphocytes. These cells can rapidly secrete large amounts of cytokines [165-167], but also exert cytotoxic properties through expression of perforin, granzymes, FasL, TRAIL and granulysin [166]. Some of these elements contribute to the pathogenesis of skin inflammatory disorders such as psoriasis [168-171]. In general, NKT-cells mediate both protective and regulatory immune functions including tumour rejection, protection against infectious microbes, maintenance of transplant tolerance and inhibition of autoimmune disease development [172]. However, in the skin, NKT-cells play an active role in diseases such as psoriasis and contact hypsersensitivity (CHS).

In humans, in the steady state, NKT-cells constitute a small proportion of lymphocytes in the skin but are expanded in psoriasis [173-176], although the exact role played by these cells is yet to be defined. Some results demonstrated a pathogenetic link between psoriatic keratinocytes, which overexpress CD1d and NKT-cells infiltrating psoriatic lesions [177,178]. Experiments in severe combined immunodeficient mice demonstrated that injection of human cells with NKT-cell characteristics into transplanted psoriatic skin could drive lesion development [177]. An increased NKT-cell density in psoriatic lesions in the epidermis compared with healthy skin was also confirmed, and CD1d expression was more extensive in psoriasis than in normal skin [179].

Activation of NKT-cells occurs during early innate stages of CHS, leading to a cascade of events such as complement activation; this generates C5a which in turn activates mast cells and platelets to release TNF-α and serotonin. This cascade results in the activation of endothelial cells to recruit T-cells locally [180]. Inhibition of the CD1d-antigen-presenting pathway to NKT-cells interferes with both initiation and effector phases of CHS [181]. NKT-cells are emerging as an important subset of lymphocytes, with a protective role in host defence and a pathogenic role in certain immune-mediated disease states.

NKT-cell: DC crosstalk: As NKT-cells are CD1d-restricted, these cells can be directly activated by CD1d-expressing cells, able to present antigen. Human and mouse CD1d are expressed at detectable levels on most cells of haematopoietic origin with high levels of expression on DC [182,183]. CD1d expression on DC is increased by the presence of inflammatory cytokines [184,185] and TLR ligation [186], but is decreased by immunoregulatory cytokines [187] and various infections of the skin [188,189]. NKT-cells can, in turn, modulate DC differentiation and function. Regulation of myeloid DC by NKT-cells in mice controls both the transition from innate to adaptive immunity and the type of T-cell responses generated [190].

γδ T-cells: γδ T-cells with invariant or restricted TCR are preferentially located within epithelial tissues that are points of contact between the body and the external environment. The unique population of γδ T-cells in the mouse epidermis are called Thy-1+ dendritic epidermal T-cells (DETC). DETC monitor epidermal cells and are poised to recognize and respond to non-peptide self-antigens expressed by neighbouring keratinocytes following tissue stress or damage; this process resembles PAMP recognitions by PRRs on DC. One example of such a self-antigen in humans is MHC class I chainrelated protein A (MICA) which is expressed on keratinocytes [191], upregulated during inflammation and infection, and recognised by NKG2D receptor expressed on γδ T-cells. Once keratinocyte distress is detected, DETC respond by local secretion of chemokines, cytotoxic effector molecules, growth factors and cytokines that orchestrate skin inflammation, tumour killing and wound-healing responses [192].

Many factors contribute to epidermal homeostasis, including skin-resident γδ T-cells [193,194]. This is partly due to expression of insulin-like growth factor (IGF-1), which mediates epidermal development and maintenance via interaction with keratinocytes [195,196]. The localization of large numbers of γδ T-cells in the skin suggests they form a first line of defence against invading pathogens, as well as contributing to tissue homeostasis. DETC (mouse epidermal γδ T-cells) play a protective role against cutaneous Staphylococcus aureus infections [197,198] and may also respond to gram-negative bacteria [199]. γδ T-cells express innate PRRs such as TLRs, enabling them to directly recognize microbial patterns [200]; indeed, DETC upregulate expression of TLR4 during cutaneous inflammation [201].

DETC can play a regulatory role in some inflammatory skin disorders; TCRδ-/- mice spontaneously develop localized dermatitis which requires the presence of αβ T-cells. Adoptive transfer experiments demonstrated DETC downregulated dermatitis in TCRδ-/-mice [202]. The underlying mechanisms of DETC regulatory function are unknown, but γδ T-cells also play a regulatory role in other inflammatory disorders. γδ T-cells can mediate downregulation of both αβ and γδ effectors in contact hypersensitivity (CHS) in vivo and IFN-γ production by the CHS effector cells in vitro [203]. γδ T-cells also have the capacity to negatively regulate αβ T-cell driven allergic IgE responses [204]. In the context of infection, γδ T-cells can play a protective role e.g. murine dermal γδ T-cells rapidly produce IL-17 following exposure to IL-1β and IL-23 [205], therefore may be key source of IL-17 following skin infection. However, a novel proinflammatory subset of human circulating IL-17-producing γδ T-cells has been recently identified in psoriasis; these cells are rapidly recruited into perturbed human skin [206].

γδ T-cell: DC crosstalk: γδ T-cells can be directly activated by DC as a proportion of γδ T-cells are CD1-restricted. CD1-restricted T-cells can also mediate the maturation of DC. Upon recognition of CD1, CD1-restricted γδ T-cells secrete TNFα and other products that, together with LPS, induce immature DC to mature and produce proinflammatory and Th1-polarizing cytokine IL-12 [207]. In human skin, expression of CD1 on DC increased significantly after Borrelia burgdorferi (the causative agent of Lyme disease) infection and in disease-specific skin lesions [208] which has implications for DC activation of γδ T-cells and bidirectional crosstalk between γδ T-cells and DC in this disease setting.

The Adaptive Immune System

The innate immune system uses a combination of PRRs to detect microbes, induce anti-microbial defence mechanisms and maintain host-microbial homeostasis. However, in vertebrates, two types of immunity are used to protect the host from infections: innate and adaptive. The adaptive immune response comprises T- and B-cell responses and employs antigen receptors that are not encoded in the germ line but are generated de novo in each organism; adaptive immune responses are highly specific.

Dendritic cells drive adaptive immunity: bridging the innate and adaptive immune system

Although the innate properties of dendritic cells (DC) and expression of PRRs allows them to recognise PAMPs on invading pathogens and DAMPs on injured/dying tissue cells, DC also possess the unique ability to initiate primary adaptive cell-mediated immune responses, generating immunological memory. DC can determine whether an active or tolerogenic immune response occurs to a particular antigen, and whether an inflammatory or tolerogenic immune response predominates [80-82,209]. DC play a role in co-stimulation of B-cells in the humoral immune response to generate antibody-secreting plasma cells [210] but, for the purpose of this review we will focus on the role of DC as being unique from other APC in their potency at initiating cell-mediated immunity (T-cell responses), focusing on DC at cutaneous sites.

T-cell responses initiated by skin dendritic cells

Epidermal dendritic cells: Langerhans’ cells: Langerhans’ cells (LC) are among the first DC to come into contact with microbial antigens; LC take up and process lipid antigens and microbial fragments for presentation to effector T-cells [211]. Human LC can preferentially induce differentiation of Th2 cells and can prime and cross-prime naive CD8+ T-cells [212]. Due to the proximity of LC to the external environment, LC were thought to have a potential role in contact hypersensitivity (CHS) reactions [213]; however removal of LC enhances CHS, suggesting LC may inhibit CHS responses [214].

LC are indeed dispensable for the induction of certain types of cellmediated immune responses, and may actually generate tolerogenic responses [215,216]. LC express surface molecules involved in the inhibition of T-cell responses such as inducible co-stimulatory molecule ligand ICOS-L (B7-H2) or the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO), both of which function as strong inducers of peripheral tolerance [28]. Our recent data characterising human DC from different tissues supports the theory of a tolerogenic role for epidermal DC, which exhibited a restricted stimulatory capacity for allogeneic T-cells compared with their blood and dermal counterparts. Such restricted stimulatory capacity was also reflected in gut DC. This is likely to be due to high antigenic load in the gut [217].

The role of LC in antimicrobial immunity has been questioned by the finding that LC were unable to generate CD8+ T-cell immunity upon cutaneous infection with herpes simplex virus (HSV) [218]. One explanation of such results was that HSV can induce LC apoptosis and therefore diminish LC function. Indeed, infection of DC with a number of different viruses can block their function e.g. during DC infection with Rauscher leukaemia virus [219], dengue virus [220], rhinoviruses [221], cytomegaloviruses [222] and HIV [223]. The role of LC in generation of T-cell responses has not yet been fully clarified, but it is likely that the immune response generated is dependent on the antigen itself and cross-talk involving other cutaneous immune cells e.g. keratinocytes as well as other LC and dermal DC (dDC).

Dermal dendritic cells: myeloid: Several subpopulations of dermal DC (dDC) have been described in humans both in the steady state and in an inflammatory context. In the steady state, the majority of dDC are of myeloid origin and express CD1c (BDCA-1) [30]. Co-expression of CD1c with CD11c is a useful marker in situ to distinguish dDC from macrophages [32]. dDC migrate rapidly to the skin-draining lymph nodes (LN) to present antigen to T-cells [29-31]; however CD1c+ dDC can be divided into at least three discrete subsets based on their surface expression of CD1a and CD14 [224].

Ex vivo isolated CD1a+CD14-dDC have a mature phenotype and are potent inducers of allogeneic naive CD4+ and CD8+ T-cell proliferation [30,212,225,226]. In contrast CD14+ dDC are less mature than CD1a+CD14- and display a reduced capacity to prime naive T-cell proliferation [33]. However, IL-23 treatment enhances T-cell stimulatory capacity of CD14+ dDC and IL-23-neutralising antibody inhibits T-cell proliferation induced by CD14-dDC [227]. These results have implications in inflammatory disease, given the importance of IL-23 in Th17 cell immunity and that dDC produce IL-23 in skin pathology [228], and may partly explain the clinical benefit observed in psoriasis patients treated with an anti-IL-12/23p40 [229;230]. CD14+ dDC are also able to polarize naive CD4+ T-cells into follicular helper T-cells, which in turn promotes naive B-cell differentiation [212].

Langerin+CD103+ DC also constitute a proportion of CD1c+ DC in the dermis; these cells are distinct from epidermal LC in both their origin and function [23,231,232] and do not represent LC en route to skin-draining LN, as previously assumed [233]. Langerin+CD103+ dDC can cross-present epidermal-derived viral and self antigens to CD8+ T-cells [234], including keratinocyte-derived antigens. Studies on langerin+CD103+ dDC raised the possibility that this DC subtype may be broadly represented in many tissues, mainly for its function in CD8+ T-cell responses and tolerance. Indeed, langerin+ DC are required for CD8+ T-cell responses to influenza in the lung, despite the presence of other DC subsets [235].

A small population of myeloid dDC have been identified that do not overlap with the CD1c+ population in normal skin. These cells constitute approximately 10% of CD11c+ dDC and can be identified by expression of CD141 (BDCA-3) [32]. In blood, these cells are also non-overlapping with the CD1c+ population, and are thought to be the least immunostimulatory myeloid blood DC population. Evidence now suggests that these CD141+ DC may be the human equivalent of mouse CD8α+ DC [236], which take up dead/dying cells, process exogenous antigen on MHC class I molecules to present to CD8+ T-cells [237-239], and induce protective CD8+ responses against cancers, viruses and other pathogenic infections [240-243].

Activated myeloid dDC participate in the inflammatory responses partly by secretion of chemokines and cytokines (as mentioned in earlier sections) but also affect T-cell polarization. Tumour necrosis factor (TNF) and inducible nitric oxide synthase (iNOS)-producing DC (TIP-DC) play a major role in psoriasis [39], partly mediated by activation and differentiation of Th17 cells [21].

Dermal dendritic cells: plasmacytoid: Human plasmacytoid DC (pDC) represent a minor population in the blood and the skin and play a major role in anti-viral immunity due to their capacity to rapidly produce large amounts of proinflammatory type I interferons (IFNs) upon viral infection [244,245], thus activating inflammatory adaptive immune responses [246]. pDC have been implicated in the pathogenesis of psoriasis, and also of systemic lupus erythematosus (SLE) [44,247]; early activation of pDC triggers innate immune responses in psoriasis resulting in pDC activation via TLR9. This in turn leads to IFNα production and activation of inflammatory adaptive immune responses [42].

Inflammatory dendritic epidermal cells: Inflammatory dendritic epidermal cells (IDEC) can populate both the epidermis and the dermis during an inflammatory immune response [37,248]. IDEC over-express the high affinity Fc receptor for IgE (FcεRI), facilitating their reactivity to IgE-bound allergens, resulting in a pro-inflammatory allergic-specific T-cell response [249].

Function of T-cells in the skin

CD4+ and CD8+ T-cells are present in approximately equal numbers in the skin, and most are memory T-cells [250]. The three main types of CD4+ Th cells have been found in the skin during various inflammatory diseases; Th1, Th2 and Th17 cells. Th1 cells are present during infections with intracellular organisms and produce IFNγ and lymphotoxin to kill such organisms. Although previously Th1 responses have been associated with autoimmunity (such as psoriasis) and Th2 responses linked with allergic diseases (such as asthma and atopic dermatitis; AD), Th17 cells also play a crucial role in both psoriasis [228] and AD [251].

Th17 cells are essential for first-line defence against various fungal and bacterial infections [45], specifically diseases which are characterised by recurrent and persistent infections of the skin and mucosal membranes [252-254]. A putative mechanism of host defence against microorganisms involving IL-17 and IL-22 in the skin is the upregulation of anti-microbial peptide (AMP) production by keratinocytes [144]. A subset of circulating T-cells with skin-homing potential that produce IL-22 but not IL-17 or IFN-γ (Th22 cells) [255,256] have also been identified in skin cell cultures from patients with AD [257], though their functional role in skin pathology and homeostasis is currently unclear.

It has been proposed that skin-resident T-cells have a role in skin immune homeostasis and pathology [258]; normal skin contains twice as many T-cells as the blood and 98% of CLA+ skin-homing lymphocytes in the body reside in the skin in the steady state [259]. Skin-resident memory T-cells play a key role in skin inflammation e.g. psoriasis [260,261] and can be activated by skin DC resulting in local proliferation of antigen-specific CD8+ T-cells during HSV infection [262]. Skin-resident memory T-cells express CD103 and VLA-1 and undergo homeostatic proliferation, and provide protection from pathogen challenge [263].

Immune cell homing and migration to the skin

General principles of T-cell homing to the skin: Lymphocytes continuously migrate around the body to meet antigens. For T-cells trafficking to lymphoid and extra-lymphoid sites, this migration involves a multi-step process, regulated by co-ordinated interactions between cell surface molecules on T-cells with their respective ligands on the surface of vascular endothelial cells [264]. Transendothelial migration into cutaneous sites is dependent on T-cell adhesion to endothelial cells, and their subsequent migration to and through endothelial cell junctions [264-266].

The trafficking pattern of T-cells changes during their transition from naive to memory T-cells. Naive T-cells constitutively traffic through lymphoid tissue while memory T-cells acquire the ability to infiltrate non-lymphoid sites, such as the skin, at the site of antigen. Upon DC stimulation, T-cells acquire the ability to express homing receptors including tissue-selective integrins and chemokine receptors allowing migration to specific organs, such as the skin.

T-cells localizing to the skin express cutaneous lymphocyteassociated antigen (CLA). CLA arises from specialized glycosylation of P-selectin glycoprotein ligand-1 (CD162) [267], thought to be involved in tissue-specific localization of cutaneous T-cells within the skin [268,269]. CLA mediates tethering and rolling of T-cells through interaction with its endothelial receptor E-selectin, constitutively expressed on skin post-capillary venules. However, interactions of Pand E-selectin with their T-cell expressed ligands are not skin-specific, suggesting a role for other skin-homing molecules.

The interaction between chemokine receptor CCR4 and its ligand CCL17 (TARC) has been implicated in skin-homing of immune cells; CCR4 is involved in vascular recognition by cutaneous but not intestinal memory T-cells [270], and is necessary for antigen-driven cutaneous accumulation of CD4+ T-cells under physiological conditions [271]. Interactions between chemokine receptor CCR10 and its ligand CCL27 (CTACK) has also been implicated in skin-homing [272]. The ligands for CCR4 and CCR10, CCL17 (TARC) and CCL27 (CTACK), have been found on inflamed and non-inflamed skin endothelium [270,273]. CCL27 (CTACK) is preferentially produced by epidermal keratinocytes [273].

Cutaneous dendritic cells imprint skin-homing properties on T-cells: DC not only activate naive T-cells to generate antigen-specific T-cell proliferation and expansion, but they also direct the T-cells to the site where antigen is most likely to be encountered, by imprinting tissue specificity. DC from skin-draining lymph nodes specifically induce expression of skin-homing markers on activated T-cells [274]. Likewise, mouse LC (epidermal DC) are specialized to target T-cells to inflamed skin [275] and our recent studies demonstrate human freshly isolated epidermal and dermal DC specifically imprint a skin-homing profile on stimulated T-cells [217]. In contrast, murine DC from secondary lymphoid tissue in the gut specifically induce gut-homing molecules α4β7 and CCR9 on activated T-cells [276-278], supported by our studies demonstrating fresh human gut DC specifically imprint a gut-homing profile on T-cells [217].

Vitamin D may promote development of DC that stimulates T-cells to express skin-homing markers. In humans, in vitro studies show vitamin D3, a pre-vitamin produced by sunlight in the skin, is itself inactive but efficiently processed to DC to its active form, 1,25(OH)2D3, which induces surface expression of the skin T-cell associated chemokine receptor CCR10. Expression of CCR10 confers an attraction to the epidermal chemokine CCL27 [272]. However, the role of vitamin D in leucocyte migration to the skin is unclear as it also downregulates CLA expression [279]. Although vitamin D can confer expression of particular skin-homing markers on T-cells, it also induces tolerogenic properties on DC [280-282]; 1,25(OH)2D3-treated DC stimulate hyporesponsive T-cell responses and generate regulatory T-cell populations (Tregs) [281-283]. These properties are likely to contribute to the immunosuppressive effects of UV light (specifically UVB) [284-286] and efficacy of UV-light therapy for inflammatory disorders such as psoriasis [287].

Migratory properties of skin dendritic cells: DC themselves must also exhibit tissue-specific properties since they control trafficking of lymphocytes (that they stimulate) and deal with different microenvironments at different sites. However, information about expression of tissue-homing markers on DC themselves is scarce, particularly in humans, primarily due to the methodological difficulties in studying human tissue.

Antigen encounter causes DC maturation and subsequent migration of DC to the peripheral LN to generate a T-cell mediated immune response [288-291]. Most models of DC migration are based on epidermal LC migration following administration of skin-sensitising agents [292], carcinogens, or upon infection [293,294]. Human studies demonstrate a dramatic change in chemokine receptor expression on DC can be induced by TLR-mediated stimulation and maturation of DC [295]. This includes up-regulation of LN-homing marker CCR7, enabling migration to secondary lymphoid organs [296].

Little information was previously available regarding the homing profile of tissue-resident DC in humans, in the steady state. However, we recently demonstrated that fresh human DC express tissue-specific homing profiles, with the ability to induce specific homing properties on T-cells. Both epidermal and dermal DC lacked expression of guthoming markers β7 integrin and CCR9 but expressed skin-homing markers CLA and CCR4, and skin-associated homing marker CCR10. The opposite was true of gut DC which expressed gut-homing markers only [217]. However, there were skin DC present that did not express skin-homing markers, suggesting skin-homing marker expression may not be essential for retention of DC within cutaneous compartments.

Epidermal LC display some unique characteristics compared with other DC. LC express particular proteinases allowing them to pass through the basement membrane, including metalloproteinases (MMPs) [297]. MMP-9 is expressed by LC and up-regulated by inflammatory cytokines TNF-α and IL-1β [298]. Migration of both LC and dermal DC (dDC) can be prevented by MMP inhibitors, MMP- 9 and MMP-2 antibodies, and by natural tissue inhibitors of MMPs (TIMPs) [299].

The Skin Microbiome

The skin is in constant contact with the external environment and hosts an ecosystem colonized by a diverse collection of microorganisms, including bacteria, fungi, viruses and mites [3-8]. Many of these microorganisms are harmless and can provide vital immunological functions; symbiotic microorganisms protect against host invasion by more pathogenic organisms. The perception of the skin as an ecosystem comprised of diverse microorganisms can be compared to the gastrointestinal (GI) tract; the GI tract is in contact with numerous commensal microbiota and diverse pathogens, and therefore a balance needs to be maintained between immunogenic or tolerogenic immune responses. Disruption of this balance at either site can result in skin disorders or infections, or inflammatory bowel diseases, infections or even cancer.

Modulation of cutaneous immune responses by the skin microbiome

The skin can discriminate between commensal microorganisms and harmful pathogenic microorganisms; mechanisms of this discrimination are not fully clear but are likely to involve DC modulation. DC in the gut are central to maintaining the balance between immunogenic or tolerogenic immune responses [300]; alterations in gut DC occur in inflammatory bowel diseases [300,301]. DC influence peripheral tolerance by promoting negative selection in the thymus [302] and generation of T-cells with regulatory properties [303].

Staphylococcus epidermidis, a commensal bacterium, has recently been demonstrated to modulate the host innate immune response. S. epidermidis products can selectively inhibit skin pathogens such as Staphylococcus aureus and Group A Streptococcus, and even co-operate with host anti-microbial peptides (AMPs) to enhance pathogen killing [304,305]. Commensal bacterial-induced TLR signalling may be necessary for cell survival and repair during infection. Lipoteichoic acid produced by S. epidermidis can inhibit skin inflammation through a TLR2 and TLR3-mediated crosstalk mechanism [306]. S. Epidermidis also triggers keratinocyte expression of AMPs through a TLR2- dependent mechanism [307].

The skin microbiome and disease

Skin diseases can be associated with a specific organism within the skin microbiome via three different mechanisms: skin disorders with a correlation to microbiota, skin disorders with a currently unidentified microbial component or a skin commensal microorganism that can become invasive to cause infection [308]. More than 90% of atopic dermatitis (AD) lesions are colonized with S. aureus on both lesional and non-lesional skin, compared with under 5% in skin samples from healthy individuals [309,310]. The most common treatments for AD include antibiotics and steroids. Dilute bleach baths to lower the bacterial load are also effective in reducing clinical severity [311].

Some skin disorders are linked with unidentified microbial components; commensal skin organisms can invade and become pathogenic in cases such as chronic wounds affecting diabetic, elderly and immobile individuals. Although these organisms do not cause the initial wound, they are thought to contribute to the lack of healing and persistent inflammation that is associated with chronic wounds [312-315]. Slow-healing diabetic mouse models demonstrate correlation between the commensal microbiota and aberrant expression of skin defence and inflammatory genes [316], likely to contribute to wound failure.

Some skin commensal microorganisms can become invasive and cause infection; S. epidermidis is a very common commensal microorganism on the skin, but is also the most frequent cause of hospital-acquired infection during administration of intrusive medical devices such as catheters or heart valves [317]. Once commensal microorganisms breach the skin barrier, virulent strains of these organisms can form biofilms, protecting them from the host immune system and antibiotics [318].


The skin immune system comprises a complex network of cells that all contribute not only to immunity against invading pathogens but also to homeostasis in the skin. The nature of immune responses generated in the skin depends on the types of antigen present, effects of environmental and genetic factors, and the interplay between components of the innate and adaptive immune systems. DC with their inherent plasticity play crucial roles in initiating and modulating immune responses, and are arguably the driving force bridging the innate and adaptive immune systems. This is due to their direct roles in both types of immune responses; however, the cross-talk between the complex network of DC subsets, skin-resident innate and adaptive immune sentinels, and accessory epidermal and dermal components also contribute to homeostasis and pathology. The role of the skin microbiome in modulating immune responses in the skin has started to be investigated; cutaneous DC are likely to play a crucial role in maintaining the balance between tolerance to harmless commensal microorganisms and immunity against harmful invading pathogens in the skin, as gut DC are known to, in the GI tract. Recent advances in the knowledge of skin DC in health and disease has led to development of therapies harnessing skin DC with specialized properties to control immunity; several therapeutic interventions targeting skin DC have proved beneficial to psoriasis patients [39,319]. However, further studies are required to fully understand the contribution of skin DC subsets in immunity and tolerance.


  1. Bos JD, Kapsenberg ML (1986) The skin immune-system - its cellular-constituents and their interactions.
  2. Noble WC (1984) Skin microbiology: coming of age. J Med Microbiol 17:1-12.
  3. Roth RR, James WD (1988) Microbial ecology of the skin. Annu Rev Microbiol 42: 441-464.
  4. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140: 805-820.
  5. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327: 291-295.
  6. Wagner H (2006) Endogenous TLR ligands and autoimmunity. Adv Immunol 91: 159-173.
  7. Shortman K, Naik SH (2007) Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7: 19-30.
  8. Harder J, Bartels J, Christophers E, Schroder JM (1997) A peptide antibiotic from human skin. Nature 387: 861.
  9. Sharp LL, Jameson JM, Witherden DA, Komori HK, Havran WL (2005) Dendritic epidermal T-cell activation. Crit Rev Immunol 25: 1-18.
  10. Sozzani S, Allavena P, Vecchi A, Mantovani A (2000) Chemokines and dendritic cell traffic. J Clin Immunol 20: 151-160.
  11. Strid J, Roberts SJ, Filler RB, Lewis JM, Kwong BY, et al. (2008) Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 9: 146-154.
  12. Nestle FO, Gilliet M (2005) Defining upstream elements of psoriasis pathogenesis: an emerging role for interferon alpha. J Invest Dermatol 125: xiv-xxv.
  13. Weinrauch Y, Drujan D, Shapiro SD, Weiss J, Zychlinsky A (2002) Neutrophil elastase targets virulence factors of enterobacteria. Nature 417: 91-94.
  14. Segal AW (2005) How neutrophils kill microbes. Annu Rev Immunol 23: 197-223.
  15. Nauseef WM (2007) How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 219: 88-102.
  16. Xu Q, Seemanapalli SV, Reif KE, Brown CR, Liang FT (2007) Increasing the recruitment of neutrophils to the site of infection dramatically attenuates Borrelia burgdorferi infectivity. J Immunol 178: 5109-5115.
  17. Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007) Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 7: 678-689.
  18. Kobayashi SD, DeLeo FR (2009) Role of neutrophils in innate immunity: a systems biology-level approach. Wiley Interdiscip Rev Syst Biol Med 1: 309-333.
  19. Corbin BD, Seeley EH, Raab A, Feldmann J, Miller MR, et al. (2008) Metal chelation and inhibition of bacterial growth in tissue abscesses. Science 319: 962-965.
  20. Molne L, Verdrengh M, Tarkowski A (2000) Role of neutrophil leukocytes in cutaneous infection caused by Staphylococcus aureus. Infect Immun 68: 6162-6167.
  21. Hidalgo-Grass C, Dan-Goor M, Maly A, Eran Y, Kwinn LA, et al. (2004) Effect of a bacterial pheromone peptide on host chemokine degradation in group A streptococcal necrotising soft-tissue infections. Lancet 363: 696-703.
  22. Hidalgo-Grass C, Mishalian I, Dan-Goor M, Belotserkovsky I, Eran Y, et al. (2006) A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues. EMBO J 25: 4628-4637.
  23. Gilad J, Borer A, Smolyakov R, Riesenberg K, Schlaeffer F, et al. (2006) Impaired neutrophil functions in the pathogenesis of an outbreak of recurrent furunculosis caused by methicillin-resistant Staphylococcus aureus among mentally retarded adults. Microbes Infect 8:1801-1805.
  24. Megiovanni AM, Sanchez F, Robledo-Sarmiento M, Morel C, Gluckman JC, et al. (2006) Polymorphonuclear neutrophils deliver activation signals and antigenic molecules to dendritic cells: a new link between leukocytes upstream of T lymphocytes. J Leukoc Biol 79: 977-988.
  25. van Gisbergen KP, Ludwig IS, Geijtenbeek TB, van KY (2005) Interactions of DC-SIGN with Mac-1 and CEACAM1 regulate contact between dendritic cells and neutrophils. FEBS Lett 579: 6159-6168.
  26. van Gisbergen KP, Sanchez-Hernandez M, Geijtenbeek TB, van KY (2005) Neutrophils mediate immune modulation of dendritic cells through glycosylation-dependent interactions between Mac-1 and DC-SIGN. J Exp Med 201: 1281-1292.
  27. Wei-yuan M, Wen-ting L, Chen Z, Qing S (2011) Significance of DC-LAMP and DC-SIGN expression in psoriasis vulgaris lesions. Exp Mol Pathol 91: 461-465.
  28. Steinman RM (1991) The dendritic cell system and its role in immunogenicity. Annu Rev Immunol 9: 271-96.
  29. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392: 245-252.
  30. Hart DN (1997) Dendritic cells: unique leukocyte populations which control the primary immune response. Blood 90: 3245-3287.
  31. Volkman A, Gowans JL (1965) The origin of macrophages from bone marrow in the rat. Br J Exp Pathol 46: 62-70.
  32. Mosser DM, Handman E (1992) Treatment of murine macrophages with interferon-gamma inhibits their ability to bind leishmania promastigotes. J Leukoc Biol 52: 369-376.
  33. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20: 197-216.
  34. Sieling PA, Modlin RL (2002) Toll-like receptors: mammalian "taste receptors" for a smorgasbord of microbial invaders. Curr Opin Microbiol 5: 70-75.
  35. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 13: 251-276.
  36. Raupach B, Kaufmann SH (2001) Immune responses to intracellular bacteria. Curr Opin Immunol 13: 417-428.
  37. Ottenhoff TH, Verreck FA, Lichtenauer-Kaligis EG, Hoeve MA, Sanal O, et al. (2002) Genetics, cytokines and human infectious disease: lessons from weakly pathogenic mycobacteria and salmonellae. Nat Genet 32: 97-105.
  38. Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, et al. (2004) Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci U S A 101:4560-4565.
  39. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25: 677-686.
  40. Mahdavian DB, van der Veer WM, van EM, Niessen FB, Beelen RH (2011) Macrophages in skin injury and repair. Immunobiology 216: 753-762.
  41. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23-35.
  42. Stein M, Keshav S, Harris N, Gordon S (1992) Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med 176: 287-292.
  43. Anderson CF, Mosser DM (2002) Cutting edge: biasing immune responses by directing antigen to macrophage Fc gamma receptors. J Immunol 168: 3697-3701.
  44. Gerber JS, Mosser DM (2011) Reversing lipopolysaccharide toxicity by ligating the macrophage Fc gamma receptors. J Immunol 166: 6861-6868.
  45. Sutterwala FS, Noel GJ, Clynes R, Mosser DM (1997) Selective suppression of interleukin-12 induction after macrophage receptor ligation. J Exp Med 185: 1977-1985.
  46. Schebesch C, Kodelja V, Müller C, Hakij N, Bisson S, et al. (1997) Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro. Immunology 92: 478-486.
  47. Goerdt S, Politz O, Schledzewski K et al. (1999) Alternative versus classical activation of macrophages. Pathobiology 67: 222-226.
  48. Rutschman R, Lang R, Hesse M, Ihle JN, Wynn TA, et al. (2001) Cutting edge: Stat6-dependent substrate depletion regulates nitric oxide production. J Immunol 166: 2173-2177.
  49. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, et al. (2001) Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol 53: 386-392.
  50. Song E, Ouyang N, Horbelt M, Antus B, Wang M, et al. (2000) Influence of alternatively and classically activated macrophages on fibrogenic activities of human fibroblasts. Cell Immunol 204: 19-28.
  51. Hesse M, Modolell M, La Flamme AC, Schito M, Fuentes JM, et al. (2001) Differential regulation of nitric oxide synthase-2 and arginase-1 by type 1/type 2 cytokines in vivo: granulomatous pathology is shaped by the pattern of L-arginine metabolism. J Immunol 167: 6533-6544.
  52. Higashi-Kuwata N, Makino T, Inoue Y, Takeya M, Ihn H (2009) Alternatively activated macrophages (M2 macrophages) in the skin of patient with localized scleroderma. Exp Dermatol 18: 727-729.
  53. Fuentes-Duculan J, Suárez-Fariñas M, Zaba LC, Nograles KE, Pierson KC, et al. (2010) A subpopulation of CD163-positive macrophages is classically activated in psoriasis. J Invest Dermatol 130: 2412-2422.
  54. Kim SO, Sheikh HI, Ha SD, Martins A, Reid G (2006) G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages. Cell Microbiol 8: 1958-1971.
  55. Roberts AW (2005) G-CSF: a key regulator of neutrophil production, but that's not all! Growth Factors 23: 33-41.
  56. Ohteki T, Suzue K, Maki C, Ota T, Koyasu S (2001) Critical role of IL-15-IL-15R for antigen-presenting cell functions in the innate immune response. Nat Immunol 2: 1138-1143.
  57. Malaviya R, Ross EA, MacGregor JI, Ikeda T, Little JR, et al. (1994) Mast cell phagocytosis of FimH-expressing enterobacteria. J Immunol 152: 1907-1914.
  58. Malaviya R, Gao Z, Thankavel K, van der Merwe PA, Abraham SN (1999) The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48. Proc Natl Acad Sci U S A 96: 8110-8115.
  59. Thakurdas SM, Melicoff E, Sansores-Garcia L, Moreira DC, Petrova Y, et al. (2007) The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J Biol Chem 282: 20809-20815.
  60. Malaviya R, Abraham SN (2000) Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis. J Leukoc Biol 67: 841-846.
  61. Pothoulakis C, Castagliuolo I, LaMont JT (1998) Nerves and Intestinal Mast Cells Modulate Responses to Enterotoxins. News Physiol Sci 13: 58-63.
  62. Askenase PW (1977) Immune inflammatory responses to parasites: the role of basophils, mast cells and vasoactive amines. Am J Trop Med Hyg 26: 96-103.
  63. Befus AD, Bienenstock J (1982) Immunity to infectious agents in the gastrointestinal tract. J Am Vet Med Assoc 181:1066-1068.
  64. Jarrett EE, Miller HR (1982) Production and activities of IgE in helminth infection. Prog Allergy 31:178-233.
  65. Wedemeyer J, Tsai M, Galli SJ (2000) Roles of mast cells and basophils in innate and acquired immunity. Curr Opin Immunol 12: 624-631.
  66. Kitamura Y, Miyoshi I (1978) Development and differentiation of mast cells and basophils. Nihon Ketsueki Gakkai Zasshi 41: 1251-1259.
  67. Kitamura Y, Yokoyama M, Matsuda H, Ohno T, Mori KJ (1981) Spleen colony-forming cell as common precursor for tissue mast cells and granulocytes. Nature 291: 159-160.
  68. Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD (1991) Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol 146: 1410-1415.
  69. Okayama Y, Kawakami T (2006) Development, migration, and survival of mast cells. Immunol Res 34: 97-115.
  70. Rodewald HR, Dessing M, Dvorak AM, Galli SJ (1996) Identification of a committed precursor for the mast cell lineage. Science 271: 818-22.
  71. Irani AA, Schechter NM, Craig SS, DeBlois G, Schwartz LB (1986) Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci U S A 83: 4464-4468.
  72. Pejler G, Knight SD, Henningsson F, Wernersson S (2009) Novel insights into the biological function of mast cell carboxypeptidase A. Trends Immunol 30: 401-408.
  73. Harvima IT, Naukkarinen A, Paukkonen K, Harvima RJ, Aalto ML, et al. (1993) Mast cell tryptase and chymase in developing and mature psoriatic lesions. Arch Dermatol Res 285: 184-192.
  74. Vliagoftis H, Befus AD (2005) Rapidly changing perspectives about mast cells at mucosal surfaces. Immunol Rev 206: 190-203.
  75. Vliagoftis H, Befus AD (2005) Mast cells at mucosal frontiers. Curr Mol Med 5: 573-589.
  76. Matsushima H, Yamada N, Matsue H, Shimada S (2004) TLR3-, TLR7-, and TLR9-mediated production of proinflammatory cytokines and chemokines from murine connective tissue type skin-derived mast cells but not from bone marrow-derived mast cells. J Immunol 173: 531-541.
  77. Kitawaki T, Kadowaki N, Sugimoto N, Kambe N, Hori T, et al. (2006) IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells. Int Immunol18: 1789-1799.
  78. Jawdat DM, Albert EJ, Rowden G, Haidl ID, Marshall JS (2004) IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J Immunol 173: 5275-5282.
  79. Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, et al. (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176: 4102-4112.
  80. Kabashima K, Narumiya S (2003) The DP receptor, allergic inflammation and asthma. Prostaglandins Leukot Essent Fatty Acids 69: 187-194.
  81. Hammad H, de Heer HJ, Soullie T, Hoogsteden HC, Trottein F, et al. (2003) Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1. J Immunol 171: 3936-3940.
  82. Galli SJ, Grimbaldeston M, Tsai M (2008) Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol 8: 478-486.
  83. Otsuka A, Kubo M, Honda T, Egawa G, Nakajima S, et al. (2011) Requirement of Interaction between Mast Cells and Skin Dendritic Cells to Establish Contact Hypersensitivity. PLoS One 6: e25538.
  84. Dudeck A, Suender CA, Kostka SL, von SE, Maurer M (2011) Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function. Eur J Immunol 41: 1883-1893.
  85. Smyth MJ, Hayakawa Y, Takeda K, Yagita H (2002) New aspects of natural-killer-cell surveillance and therapy of cancer. Nat Rev Cancer 2: 850-861.
  86. Sivori S, Falco M, Della CM, Carlomagno S, Vitale M, et al. (2004) CpG and double-stranded RNA trigger human NK cells by Toll-like receptors: induction of cytokine release and cytotoxicity against tumors and dendritic cells. Proc Natl Acad Sci U S A 101: 10116-10121.
  87. Ottaviani C, Nasorri F, Bedini C, de PO, Girolomoni G, et al. (2006) CD56brightCD16(-) NK cells accumulate in psoriatic skin in response to CXCL10 and CCL5 and exacerbate skin inflammation. Eur J Immunol 36: 118-128.
  88. Carbone T, Nasorri F, Pennino D, Eyerich K, Foerster S, et al. (2010) CD56highCD16-CD62L- NK cells accumulate in allergic contact dermatitis and contribute to the expression of allergic responses. J Immunol 184: 1102-1110.
  89. Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, et al. (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436: 709-713.
  90. Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203: 2271-2279.
  91. Lowes MA, Kikuchi T, Fuentes-Duculan J, Cardinale I, Zaba LC, et al. (2008) Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 128: 1207-1211.
  92. Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, et al. (2007) Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445: 648-651.
  93. Boniface K, Blom B, Liu YJ, de Waal MR (2008) From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. Immunol Rev 226: 132-146.
  94. Langrish CL, McKenzie BS, Wilson NJ, de Waal MR, Kastelein RA, et al. (2004) IL-12 and IL-23: master regulators of innate and adaptive immunity. Immunol Rev 202: 96-105.
  95. Piskin G, Sylva-Steenland RM, Bos JD, Teunissen MB (2006) In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol 176: 1908-1915.
  96. Luci C, Reynders A, Ivanov II, Cognet C, Chiche L, et al. (2009) Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol 10: 75-82.
  97. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, et al. (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29: 958-970.
  98. Cella M, Fuchs A, Vermi W, Facchetti F, Otero K, et al. (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457: 722-725.
  99. Ma HL, Liang S, Li J, Napierata L, Brown T, et al. (2008) IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 118: 597-607.
  100. Wolk K, Witte E, Warszawska K, Schulze-Tanzil G, Witte K, et al. (2009) The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur J Immunol 39: 3570-3581.
  101. Vivier E, Spits H, Cupedo T (2009) Interleukin-22-producing innate immune cells: new players in mucosal immunity and tissue repair? Nat Rev Immunol 9: 229-234.
  102. Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, et al. (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206: 35-41.
  103. Wehner R, Dietze K, Bachmann M, Schmitz M (2011) The bidirectional crosstalk between human dendritic cells and natural killer cells. J Innate Immun 3: 258-263.
  104. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, et al. (2002) Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med 195: 327-333.
  105. Borg C, Terme M, Taieb J, Ménard C, Flament C, et al. (2004) Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J Clin Invest 114: 379-388.
  106. Walzer T, Dalod M, Vivier E, Zitvogel L (2005) Natural killer cell-dendritic cell crosstalk in the initiation of immune responses. Expert Opin Biol Ther 5: S49-S59.
  107. Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van KL (2004) NKT cells: what's in a name? Nat Rev Immunol 4: 231-237.
  108. Gumperz JE (2004) Antigen specificity of semi-invariant CD1d-restricted T cell receptors: the best of both worlds? Immunol Cell Biol 82: 285-294.
  109. Godfrey DI, Kronenberg M (2004) Going both ways: immune regulation via CD1d-dependent NKT cells. J Clin Invest 114: 1379-1388.
  110. Godfrey DI, Pellicci DG, Smyth MJ (2004) Immunology. The elusive NKT cell antigen--is the search over? Science 306: 1687-1689.
  111. Swann J, Crowe NY, Hayakawa Y, Godfrey DI, Smyth MJ (2004) Regulation of antitumour immunity by CD1d-restricted NKT cells. Immunol Cell Biol 82: 323-331.
  112. Seino K, Taniguchi M (2004) Functionally distinct NKT cell subsets and subtypes. J Exp Med 202: 1623-1626.
  113. Linsen L, Somers V, Stinissen P (2005) Immunoregulation of autoimmunity by natural killer T cells. Hum Immunol 66: 1193-1202.
  114. Prpic ML, Kastelan M, Laskarin G, Zamolo G, Massari D, et al. (2007) Analysis of perforin expression in peripheral blood and lesions in severe and mild psoriasis. J Dermatol Sci 47: 29-36.
  115. Kastelan M, Prpic ML, Gruber F, Zamolo G, Zauhar G, et al. (2004) Perforin expression is upregulated in the epidermis of psoriatic lesions. Br J Dermatol 151: 831-836.
  116. Raychaudhuri SP, Jiang WY, Raychaudhuri SK, Krensky AM (2004) Lesional T cells and dermal dendrocytes in psoriasis plaque express increased levels of granulysin. J Am Acad Dermatol 51: 1006-1008.
  117. Yawalkar N, Schmid S, Braathen LR, Pichler WJ (2001) Perforin and granzyme B may contribute to skin inflammation in atopic dermatitis and psoriasis. Br J Dermatol 144: 1133-1139.
  118. Taniguchi M, Harada M, Kojo S, Nakayama T, Wakao H (2003) The regulatory role of Valpha14 NKT cells in innate and acquired immune response. Annu Rev Immunol 21: 483-513.
  119. Bonish B, Jullien D, Dutronc Y, Huang BB, Modlin R, et al. (2000) Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. J Immunol 165: 4076-4085.
  120. Cameron AL, Kirby B, Fei W, Griffiths CE (2002) Natural killer and natural killer-T cells in psoriasis. Arch Dermatol Res 294: 363-369.
  121. Vissers WH, Arndtz CH, Muys L, Van Erp PE, de Jong EM, et al. (2004) Memory effector (CD45RO+) and cytotoxic (CD8+) T cells appear early in the margin zone of spreading psoriatic lesions in contrast to cells expressing natural killer receptors, which appear late. Br J Dermatol 150: 852-859.
  122. Curry JL, Qin JZ, Bonish B, Carrick R, Bacon P, et al. (2003) Innate immune-related receptors in normal and psoriatic skin. Arch Pathol Lab Med 127: 178-186.
  123. Nickoloff BJ, Bonish B, Huang BB, Porcelli SA (2000) Characterization of a T cell line bearing natural killer receptors and capable of creating psoriasis in a SCID mouse model system. J Dermatol Sci 24: 212-225.
  124. Bonish B, Jullien D, Dutronc Y, Huang BB, Modlin R, et al. (2000) Overexpression of CD1d by keratinocytes in psoriasis and CD1d-dependent IFN-gamma production by NK-T cells. J Immunol 165: 4076-4085.
  125. Zhao Y, Fishelevich R, Petrali JP, Zheng L, Anatolievna MA, et al. (2008) Activation of keratinocyte protein kinase C zeta in psoriasis plaques. J Invest Dermatol 128: 2190-2197.
  126. Balato A, Unutmaz D, Gaspari AA (2009) Natural killer T cells: an unconventional T-cell subset with diverse effector and regulatory functions. J Invest Dermatol 129:1628-1642.
  127. Nieuwenhuis EE, Gillessen S, Scheper RJ, Exley MA, Taniguchi M, et al. (2005) CD1d and CD1d-restricted iNKT-cells play a pivotal role in contact hypersensitivity. Exp Dermatol 14: 250-258.
  128. Exley M, Garcia J, Wilson SB, Spada F, Gerdes D, et al. (2000) CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes. Immunology 100: 37-47.
  129. Gerlini G, Hefti HP, Kleinhans M, Nickoloff BJ, Burg G, et al. (2001) Cd1d is expressed on dermal dendritic cells and monocyte-derived dendritic cells. J Invest Dermatol 117: 576-582.
  130. Raghuraman G, Geng Y, Wang CR (2006) IFN-beta-mediated up-regulation of CD1d in bacteria-infected APCs. J Immunol 177: 7841-7848.
  131. Colgan SP, Morales VM, Madara JL, Polischuk JE, Balk SP, et al. (1996) IFN-gamma modulates CD1d surface expression on intestinal epithelia. Am J Physiol 271: C276-C283.
  132. Roura-Mir C, Wang L, Cheng TY, Matsunaga I, Dascher CC, et al. (2005) Mycobacterium tuberculosis regulates CD1 antigen presentation pathways through TLR-2. J Immunol 175: 1758-1766.
  133. Ronger-Savle S, Valladeau J, Claudy A, Schmitt D, Peguet-Navarro J, et al. (2005) TGFbeta inhibits CD1d expression on dendritic cells. J Invest Dermatol 124: 116-118.
  134. Yuan W, Dasgupta A, Cresswell P (2006) Herpes simplex virus evades natural killer T cell recognition by suppressing CD1d recycling. Nat Immunol 7: 835-842.
  135. Amprey JL, Spath GF, Porcelli SA (2004) Inhibition of CD1 expression in human dendritic cells during intracellular infection with Leishmania donovani. Infect Immun 72: 589-592.
  136. Racke FK, Clare-Salzer M, Wilson SB (2002) Control of myeloid dendritic cell differentiation and function by CD1d-restricted (NK) T cells. Front Biosci 7: d978-d985.
  137. Zwirner NW, Dole K, Stastny P (1999) Differential surface expression of MICA by endothelial cells, fibroblasts, keratinocytes, and monocytes. Hum Immunol 60: 323-330.
  138. Macleod AS, Havran WL (2011) Functions of skin-resident ?dT cells. Cell Mol Life Sci 68: 2399-2408.
  139. Jameson JM, Sharp LL, Witherden DA, Havran WL (2004) Regulation of skin cell homeostasis by gamma delta T cells. Front Biosci 9: 2640-2651.
  140. Sharp LL, Jameson JM, Cauvi G, Havran WL (2005) Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1. Nat Immunol 6: 73-79.
  141. Edmondson SR, Thumiger SP, Werther GA, Wraight CJ (2003) Epidermal homeostasis: the role of the growth hormone and insulin-like growth factor systems. Endocr Rev 24: 737-764.
  142. Su HY, Cheng WT, Chen SC, Lin CT, Lien YY, et al. (2004) Mouse keratinocytes express c98, a novel gene homologous to bcl-2, that is stimulated by insulin-like growth factor 1 and prevents dexamethasone-induced apoptosis. Biochim Biophys Acta 1676: 127-137.
  143. Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, et al. (2010) IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J Clin Invest 120: 1762-1773.
  144. Mölne L, Corthay A, Holmdahl R, Tarkowski A (2003) Role of gamma/delta T cell receptor-expressing lymphocytes in cutaneous infection caused by Staphylococcus aureus. Clin Exp Immunol 132: 209-215.
  145. Leclercq G, Plum J (1995) Stimulation of TCR V gamma 3 cells by gram-negative bacteria. J Immunol 154: 5313-5319.
  146. Martin B, Hirota K, Cua DJ, Stockinger B, Veldhoen M (2009) Interleukin-17-producing gammadelta T cells selectively expand in response to pathogen products and environmental signals. Immunity 31: 321-330.
  147. Shimura H, Nitahara A, Ito A, Tomiyama K, Ito M, et al. (2005) Up-regulation of cell surface Toll-like receptor 4-MD2 expression on dendritic epidermal T cells after the emigration from epidermis during cutaneous inflammation. J Dermatol Sci 37: 101-110.
  148. Girardi M, Lewis J, Glusac E, Filler RB, Geng L, et al. (2002) Resident skin-specific gammadelta T cells provide local, nonredundant regulation of cutaneous inflammation. J Exp Med 195: 855-867.
  149. Szczepanik M, Anderson LR, Ushio H, Ptak W, Owen MJ, et al. (1996) Gamma delta T cells from tolerized alpha beta T cell receptor (TCR)-deficient mice inhibit contact sensitivity-effector T cells in vivo, and their interferon-gamma production in vitro. J Exp Med 184: 2129-2139.
  150. McMenamin C, Pimm C, McKersey M, Holt PG (1994) Regulation of IgE responses to inhaled antigen in mice by antigen-specific gamma delta T cells. Science 265: 1869-1871.
  151. Gray EE, Suzuki K, Cyster JG (2011) Cutting edge: Identification of a motile IL-17-producing gammadelta T cell population in the dermis. J Immunol 186: 6091-6095.
  152. Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, et al. (2011) Identification of a novel proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a potential role in psoriasis. J Immunol 187: 2783-2793.
  153. Leslie DS, Vincent MS, Spada FM, Das H, Sugita M, et al. (2002) CD1-mediated gamma/delta T cell maturation of dendritic cells. J Exp Med 196: 1575-1584.
  154. Yakimchuk K, Roura-Mir C, Magalhaes KG, de Jong A, Kasmar AG, et al. (2011) Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-beta. Eur J Immunol 41: 694-705.
  155. Bell D, Young JW, Banchereau J (1999) Dendritic cells. Adv Immunol 72: 255-324.
  156. Jego G, Pascual V, Palucka AK, Banchereau J (2005) Dendritic cells control B cell growth and differentiation. Curr Dir Autoimmun 8: 124-139.
  157. Hunger RE, Sieling PA, Ochoa MT, Sugaya M, Burdick AE, et al. (2004) Langerhans cells utilize CD1a and langerin to efficiently present nonpeptide antigens to T cells. J Clin Invest 113: 701-708.
  158. Klechevsky E, Morita R, Liu M, Cao Y, Coquery S, et al. (2008) Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29: 497-510.
  159. Schuler G, Steinman RM (1985) Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro. J Exp Med 161: 526-546.
  160. Grabbe S, Steinbrink K, Steinert M, Luger TA, Schwarz T (1995) Removal of the majority of epidermal Langerhans cells by topical or systemic steroid application enhances the effector phase of murine contact hypersensitivity. J Immunol 155: 4207-4217.
  161. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21: 685-711.
  162. Kaplan DH, Kissenpfennig A, Clausen BE (2008) Insights into Langerhans cell function from Langerhans cell ablation models. Eur J Immunol 38: 2369-2376.
  163. Mann ER, Bernardo D, Al-Hassi HO, English NR, Clark SK, et al. (2011) Human gut-specific homeostatic dendritic cells are generated from blood precursors by the gut microenvironment. Inflamm Bowel Dis.
  164. Allan RS, Smith CM, Belz GT, van Lint AL, Wakim LM, et al. (2003) Epidermal viral immunity induced by CD8alpha+ dendritic cells but not by Langerhans cells. Science 301: 1925-1928.
  165. Gabrilovich DI, Woods GM, Patterson S, Harvey JJ, Knight SC (1994) Retrovirus-induced immunosuppression via blocking of dendritic cell migration and down-regulation of adhesion molecules. Immunology 82: 82-87.
  166. Ho LJ, Hung LF, Weng CY, Wu WL, Chou P, et al. (2005) Dengue virus type 2 antagonizes IFN-alpha but not IFN-gamma antiviral effect via down-regulating Tyk2-STAT signaling in the human dendritic cell. J Immunol 174: 8163-8172.
  167. Kirchberger S, Majdic O, Steinberger P, Blüml S, Pfistershammer K, et al. (2005) Human rhinoviruses inhibit the accessory function of dendritic cells by inducing sialoadhesin and B7-H1 expression. J Immunol 175: 1145-1152.
  168. Benedict CA, Loewendorf A, Garcia Z, Blazar BR, Janssen EM (2008) Dendritic cell programming by cytomegalovirus stunts naive T cell responses via the PD-L1/PD-1 pathway. J Immunol 180: 4836-4847.
  169. Melki MT, Saidi H, Dufour A, Olivo-Marin JC, Gougeon ML (2010) Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk--a pivotal role of HMGB1. PLoS Pathoq 6: e1000862.
  170. Angel CE, George E, Brooks AE, Ostrovsky LL, Brown TL, et al. (2006) Cutting edge: CD1a+ antigen-presenting cells in human dermis respond rapidly to CCR7 ligands. J Immunol 176: 5730-5734.
  171. Haniffa M, Ginhoux F, Wang XN, Bigley V, Abel M, et al. (2009) Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. J Exp Med 206: 371-385.
  172. Morelli AE, Rubin JP, Erdos G, Tkacheva OA, Mathers AR, et al. (2005) CD4+ T cell responses elicited by different subsets of human skin migratory dendritic cells. J Immunol 175: 7905-7915.
  173. Di Cesare A, Di Meglio P, Nestle FO (2009) The IL-23/Th17 axis in the immunopathogenesis of psoriasis. J Invest Dermatol 129: 1339-1350.
  174. Leonardi CL, Kimball AB, Papp KA, Yeilding N, Guzzo C, et al. (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371: 1665-1674.
  175. Papp KA, Langley RG, Lebwohl M, Krueger GG, Szapary P, et al. (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371: 1675-1684.
  176. Ginhoux F, Collin MP, Bogunovic M, Abel M, Leboeuf M, et al. (2007) Blood-derived dermal langerin+ dendritic cells survey the skin in the steady state. J Exp Med 204: 3133-3146.
  177. Poulin LF, Henri S, de Bovis B, Devilard E, Kissenpfennig A, et al. (2007) The dermis contains langerin+ dendritic cells that develop and function independently of epidermal Langerhans cells. J Exp Med 204: 3119-3131.
  178. Romani N, Ratzinger G, Pfaller K, Salvenmoser W, Stössel H, et al. (2001) Migration of dendritic cells into lymphatics-the Langerhans cell example: routes, regulation, and relevance. Int Rev Cytol 207: 237-270.
  179. Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L, et al. (2009) Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 10: 488-495.
  180. GeurtsvanKessel CH, Willart MA, van Rijt LS, Muskens F, Kool M, et al. (2008) Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells. J Exp Med 205: 1621-1634.
  181. Jongbloed SL, Kassianos AJ, McDonald KJ, Clark GJ, Ju X, et al. (2010) Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens. J Exp Med 207: 1247-1260.
  182. den Haan JM, Lehar SM, Bevan MJ (2000) CD8(+) but not CD8(-) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 192: 1685-1696.
  183. Iyoda T, Shimoyama S, Liu K, Omatsu Y, Akiyama Y, et al. (2002) The CD8+ dendritic cell subset selectively endocytoses dying cells in culture and in vivo. J Exp Med 195: 1289-1302.
  184. Schnorrer P, Behrens GM, Wilson NS, Pooley JL, Smith CM, et al. (2006) The dominant role of CD8+ dendritic cells in cross-presentation is not dictated by antigen capture. Proc Natl Acad Sci U S A 103: 10729-10734.
  185. Dudziak D, Kamphorst AO, Heidkamp GF, Buchholz VR, Trumpfheller C, et al. (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315: 107-111.
  186. Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, et al. (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322: 1097-1100.
  187. Lopez-Bravo M, Ardavin C (2008) In vivo induction of immune responses to pathogens by conventional dendritic cells. Immunity 29: 343-351.
  188. Naik SH (2008) Demystifying the development of dendritic cell subtypes, a little. Immunol Cell Biol 86: 439-452.
  189. Cella M, Jarrossay D, Facchetti F, Alebardi O, Nakajima H, et al. (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5: 919-923.
  190. Siegal FP, Kadowaki N, Shodell M, Fitzgerald-Bocarsly PA, Shah K, et al. (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284: 1835-1837.
  191. Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23: 307-336.
  192. Nestle FO, Nickoloff BJ (2005) From classical mouse models of psoriasis to a spontaneous xenograft model featuring use of AGR mice. Ernst Schering Res Found Workshop 50: 203-212.
  193. Wollenberg A, Wagner M, Günther S, Towarowski A, Tuma E, et al. (2002) Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119: 1096-1102.
  194. Bieber T (2007) The pro- and anti-inflammatory properties of human antigen-presenting cells expressing the high affinity receptor for IgE (Fc epsilon RI). Immunobiology 212: 499-503.
  195. Bos JD, Kapsenberg ML (1993) The skin immune system: progress in cutaneous biology. Immunol Today 14: 75-78.
  196. Di Cesare A, Di Meglio P, Nestle FO (2008) A role for Th17 cells in the immunopathogenesis of atopic dermatitis? J Invest Dermatol 128: 2569-2571.
  197. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, et al. (2008) Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med 205: 1543-1550.
  198. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, et al. (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452: 773-776.
  199. Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, et al. (2008) Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol 128: 2640-2645.
  200. Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10: 857-863.
  201. Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10: 864-871.
  202. Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, et al. (2009) IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol 123: 1244-1252.
  203. Boyman O, Conrad C, Tonel G, Gilliet M, Nestle FO (2007) The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol 28: 51-57.
  204. Clark RA, Chong B, Mirchandani N, Brinster NK, Yamanaka K, et al. (2006) The vast majority of CLA+ T cells are resident in normal skin. J Immunol 176: 4431-4439.
  205. Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, et al. (2004) Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J Exp Med 199: 731-736.
  206. Conrad C, Boyman O, Tonel G, Tun-Kyi A, Laggner U, et al. (2007) Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med 13: 836-842.
  207. Wakim LM, Waithman J, van Rooijen N, Heath WR, Carbone FR (2008) Dendritic cell-induced memory T cell activation in nonlymphoid tissues. Science; 319: 198-202.
  208. Gebhardt T, Wakim LM, Eidsmo L, Reading PC, Heath WR, et al. (2009) Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat Immunol 10: 524-530.
  209. Fabbri M, Bianchi E, Fumagalli L, Pardi R (1999) Regulation of lymphocyte traffic by adhesion molecules. Inflamm Res 48: 239-246.
  210. Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272: 60-66.
  211. Nourshargh S, Marelli-Berg FM (2005) Transmigration through venular walls: a key regulator of leukocyte phenotype and function. Trends Immunol 26: 157-165.
  212. Fuhlbrigge RC, Kieffer JD, Armerding D, Kupper TS (1997) Cutaneous lymphocyte antigen is a specialized form of PSGL-1 expressed on skin-homing T cells. Nature 389: 978-981.
  213. Picker LJ, Michie SA, Rott LS, Butcher EC (1990) A unique phenotype of skin-associated lymphocytes in humans. Preferential expression of the HECA-452 epitope by benign and malignant T cells at cutaneous sites. Am J Pathol 136: 1053-1068.
  214. Picker LJ, Kishimoto TK, Smith CW, Warnock RA, Butcher EC (1991) ELAM-1 is an adhesion molecule for skin-homing T cells. Nature 349: 796-799.
  215. Campbell JJ, Haraldsen G, Pan J, Rottman J, Qin S, et al. (1999) The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400:776-780.
  216. Campbell JJ, O'Connell DJ, Wurbel MA (2007) Cutting Edge: Chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions. J Immunol 178: 3358-3362.
  217. Sigmundsdottir H, Pan J, Debes GF, Alt C, Habtezion A, et al. (2007) DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat.Immunol 8: 285-293.
  218. Morales J, Homey B, Vicari AP, Hudak S, Oldham E, et al. (1999) CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells. Proc Natl Acad Sci U S A 96: 14470-14475.
  219. Campbell DJ, Butcher EC (2002) Rapid acquisition of tissue-specific homing phenotypes by CD4(+) T cells activated in cutaneous or mucosal lymphoid tissues. J Exp Med 195: 135-141.
  220. Dudda JC, Simon JC, Martin S (2004) Dendritic cell immunization route determines CD8+ T cell trafficking to inflamed skin: role for tissue microenvironment and dendritic cells in establishment of T cell-homing subsets. J Immunol 172: 857-863.
  221. Stagg AJ, Kamm MA, Knight SC (2002) Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur J Immunol 32: 1445-1454.
  222.  Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Márquez G, et al. (2003) Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med 198: 963-969.
  223. Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, et al. (2003) Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424: 88-93.
  224. Yamanaka K, Dimitroff CJ, Fuhlbrigge RC, Kakeda M, Kurokawa I, et al. (2008) Vitamins A and D are potent inhibitors of cutaneous lymphocyte-associated antigen expression. J Allergy Clin Immunol 121:148-157.
  225. Adorini L, Penna G (2009) Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol 70: 345-352.
  226. Penna G, Adorini L (2000) 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405-2411.
  227. van Halteren AG, van Etten E, de Jong EC, Bouillon R, Roep BO, et al. (2002) Redirection of human autoreactive T-cells Upon interaction with dendritic cells modulated by TX527, an analog of 1,25 dihydroxyvitamin D(3). Diabetes 51: 2119-2125.
  228. Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, et al. (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106: 3490-3497.
  229. Beissert S, Schwarz T (1999) Mechanisms involved in ultraviolet light-induced immunosuppression. J Investig Dermatol Symp Proc 4: 61-64.
  230. Nghiem DX, Kazimi N, Mitchell DL, Vink AA, Ananthaswamy HN, et al. (2002) Mechanisms underlying the suppression of established immune responses by ultraviolet radiation. J Invest Dermatol 119: 600-608.
  231. Ullrich SE (2002) Photoimmune suppression and photocarcinogenesis. Front Biosci 7: d684-d703.
  232. Bonis B, Kemeny L, Dobozy A, Bor Z, Szabo G, et al. (1997) 308 nm UVB excimer laser for psoriasis. Lancet 350:1522.
  233. Moll H, Fuchs H, Blank C, Rollinghoff M (1993) Langerhans cells transport Leishmania major from the infected skin to the draining lymph node for presentation to antigen-specific T cells. Eur J Immunol 23: 1595-1601.
  234. Martín P, Ruiz SR, del Hoyo GM, Anjuère F, Vargas HH et al. (2002) Dramatic increase in lymph node dendritic cell number during infection by the mouse mammary tumor virus occurs by a CD62L-dependent blood-borne DC recruitment. Blood 99:1282-1288.
  235. Diacovo TG, Blasius AL, Mak TW, Cella M, Colonna M (2005) Adhesive mechanisms governing interferon-producing cell recruitment into lymph nodes. J Exp Med 202: 687-696.
  236. Yoneyama H, Matsuno K, Zhang Y, Nishiwaki T, Kitabatake M, et al. (2004) Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int Immunol 16: 915-928.
  237. Macatonia SE, Knight SC, Edwards AJ, Griffiths S, Fryer P (1987) Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. Functional and morphological studies. J Exp Med 166: 1654-1667.
  238. Dandie GW, Watkins FY, Ragg SJ, Holloway PE, Muller HK (1994) The migration of Langerhans' cells into and out of lymph nodes draining normal, carcinogen and antigen-treated sheep skin. Immunol Cell Biol 72: 79-86.
  239. Merad M, Fong L, Bogenberger J, Engleman EG (2000) Differentiation of myeloid dendritic cells into CD8alpha-positive dendritic cells in vivo. Blood 96: 1865-1872.
  240. Sallusto F, Schaerli P, Loetscher P, Schaniel C, Lenig D, et al. (1998) Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur J Immunol 28:2760-2769.
  241. Dieu MC, Vanbervliet B, Vicari A, Bridon JM, Oldham E, et al. (1998) Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J Exp Med 188: 373-386.
  242. Salmi M, Jalkanen S (2005) Cell-surface enzymes in control of leukocyte trafficking. Nat Rev Immunol 5: 760-771.
  243. Saren P, Welgus HG, Kovanen PT (1996) TNF-alpha and IL-1beta selectively induce expression of 92-kDa gelatinase by human macrophages. J Immunol 157: 4159-4165.
  244. Ratzinger G, Stoitzner P, Ebner S, Lutz MB, Layton GT, et al. (2002) Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin. J Immunol 168: 4361-4371.
  245. Hart AL, Al-Hassi HO, Rigby RJ, Bell SJ, Emmanuel AV et al. (2005) Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 129: 50-65.
  246. Verstege MI, ten Kate FJ, Reinartz SM, van Drunen CM, Slors FJ, et al. (2008) Dendritic cell populations in colon and mesenteric lymph nodes of patients with Crohn's disease. J Histochem Cytochem 56: 233-241.
  247. Brocker T, Riedinger M, Karjalainen K (1997) Targeted expression of major histocompatibility complex (MHC) class II molecules demonstrates that dendritic cells can induce negative but not positive selection of thymocytes in vivo. J Exp Med 185: 541-550.
  248. Dhodapkar MV, Steinman RM (2002) Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. Blood 100: 174-177.
  249. Cogen AL, Yamasaki K, Sanchez KM, Dorschner RA, Lai Y, et al. (2010) Selective antimicrobial action is provided by phenol-soluble modulins derived from Staphylococcus epidermidis, a normal resident of the skin. J Invest Dermatol 130: 192-200.
  250. Cogen AL, Yamasaki K, Muto J, Sanchez KM, Crotty Alexander L, et al. (2010) Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group A Streptococcus. PLoS One 5: e8557.
  251. Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, et al. (2009) Commensal bacteria regulate Toll-like receptor 3-dependent inflammation after skin injury. Nat Med 15:1377-1382.
  252. Lai Y, Cogen AL, Radek KA, Park HJ, Macleod DT, et al. (2010) Activation of TLR2 by a small molecule produced by Staphylococcus epidermidis increases antimicrobial defense against bacterial skin infections. J Invest Dermatol 130: 2211-2221.
  253. Grice EA, Segre JA (2011) The skin microbiome. Nat Rev Microbiol 9: 244-253.
  254. Hanifin JM, Rogge JL (1977) Staphylococcal infections in patients with atopic dermatitis. Arch Dermatol 113:1383-1386.
  255. Leyden JJ, Marples RR, Kligman AM (1974) Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol 90: 525-530.
  256. Huang JT, Abrams M, Tlougan B, Rademaker A, Paller AS (2009) Treatment of Staphylococcus aureus colonization in atopic dermatitis decreases disease severity. Pediatrics 123: e808-e814.
  257. Frank DN, Wysocki A, Specht-Glick DD, Rooney A, Feldman RA et al. (2009) Microbial diversity in chronic open wounds. Wound Repair Regen 17: 163-72.
  258. Dowd SE, Sun Y, Secor PR, Rhoads DD, Wolcott BM, et al. (2008) Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol 8:43.
  259. Smith DM, Snow DE, Rees E, Zischkau AM, Hanson JD, et al. (2010) Evaluation of the bacterial diversity of pressure ulcers using bTEFAP pyrosequencing. BMC Med Genomics 3:41.
  260. Price LB, Liu CM, Melendez JH, Frankel YM, Engelthaler D, et al. (2009) Community analysis of chronic wound bacteria using 16S rRNA gene-based pyrosequencing: impact of diabetes and antibiotics on chronic wound microbiota. PLoS One 4: e6462.
  261. Grice EA, Snitkin ES, Yockey LJ, Bermudez DM, Liechty KW, et al. (2010) Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response. Proc Natl Acad Sci U S A 107:14799-804.
  262. Uckay I, Pittet D, Vaudaux P, Sax H, Lew D, et al. (2009) Foreign body infections due to Staphylococcus epidermidis. Ann Med 41:109-119.
  263. Otto M (2009) Staphylococcus epidermidis--the 'accidental' pathogen. Nat Rev Microbiol 7: 555-567.
  264. Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T, et al. (2005) Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci USA 102: 2075-2080.
Citation: Mann ER, Smith KM, Bernardo D, Al-Hassi HO, Knight SC, et al. (2012) Review: Skin and the Immune System. J Clin Exp Dermatol Res S2:003.

Copyright: © 2012 Mann ER, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.