The Journal of Allergy and Clinical Immunology
Volume 125, Issue 1 , Pages 60-68, January 2010

Natural killer cells in atopic and autoimmune diseases of the skin

  • Dagmar von Bubnoff, MD

      Affiliations

    • Department of Dermatology and Allergy, Friedrich-Wilhelms-University, Bonn, Germany
    • ,
  • Emmanuel Andrès, MD

      Affiliations

    • Department of Internal Medicine, Medical Clinic B, University Hospitals of Strasbourg, Strasbourg, France
    • ,
  • François Hentges, MD

      Affiliations

    • Laboratory of Immunogenetics and Allergology, Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg City, Luxembourg
    • ,
  • Thomas Bieber, MD

      Affiliations

    • Department of Dermatology and Allergy, Friedrich-Wilhelms-University, Bonn, Germany
    • ,
  • Tatiana Michel, PhD

      Affiliations

    • Laboratory of Immunogenetics and Allergology, Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg City, Luxembourg
    • ,
  • Jacques Zimmer, MD, PhD

      Affiliations

    • Laboratory of Immunogenetics and Allergology, Centre de Recherche Public de la Santé (CRP-Santé), Luxembourg City, Luxembourg
    • Corresponding Author InformationReprint requests: Jacques Zimmer, MD, PhD, Laboratory of Immunogenetics and Allergology, Centre de Recherche Public de la Santé (CRP-Santé), 84 Val Fleuri, L-1526 Luxembourg.

Received 4 November 2009; accepted 4 November 2009.

Article Outline

Natural killer (NK) cells are best known for their ability to recognize and kill tumor cells and virally infected cells and for their ability to produce large amounts of some cytokines, such as IFN-γ. Recent research has substantially expanded our view on the function of NK cells in the immune system in health and disease. In addition to the better-studied functions in cancer and autoimmunity, contributions from NK cells to allergies and various skin diseases have emerged. We briefly recount the traditional NK cell functions before focusing on their roles in atopic dermatitis, psoriasis, alopecia areata, and pemphigus vulgaris. Although this field is still developing, strong data are available that indicate NK cell involvement. In patients with allergic diseases, the production of TH2 cytokines by NK cells contributes to the known immune deviation. In patients with psoriasis, their pathophysiologic role seems to be especially the production of IFN-γ. NK cell overactivation can be found in patients with alopecia areata and pemphigus vulgaris. Many details are still unclear; however, we believe that there is solid evidence that NK cells actively participate in a number of diseases that have not been traditionally linked to this type of lymphocyte.

Key words: Natural killer cells, skin, allergy, autoimmunity

Abbreviations used: AA, Alopecia areata, AD, Atopic dermatitis, AR, Activating receptor, CHS, Contact hypersensitivity, CMV, Cytomegalovirus, DC, Dendritic cell, IDEC, Inflammatory dendritic epidermal cell, ILT2, Immunoglobulin-like transcript 2, IP, Immune privilege, IR, Inhibitory receptor, KIR, Killer immunoglobulin receptor, LC, Langerhans cell, LTi, Lymphoid tissue inducer, MICA, MHC class I chain-related protein, MIF, Macrophage migration inhibitory factor, NK, Natural killer, NKT, Natural killer T, PNM, Proximal nail matrix, PV, Pemphigus vulgaris, Tip-DC, Dendritic cell (CD11c+CD1c–) that secretes TNF-α and produces inducible nitric oxide synthase

 

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Natural killer cells 

Definition and functions of natural killer cells 

Natural killer (NK) cells are a third type of lymphocyte in addition to T and B cells. In human subjects they are phenotypically defined as CD3−CD56+ lymphocytes. The major functional properties of NK cells are cytotoxicity and cytokine production. Cytotoxicity can be further subdivided into (1) natural cytotoxic activity predominantly directed toward tumor cells and virally infected cells in the absence of prior stimulation or immunization and (2) antibody-dependent cellular cytotoxicity directed against antibody-coated target cells.1, 2, 3, 4, 5, 6 In this situation the constant part of the antibody triggers the Fcγ receptor CD16. Although present in resting NK cells, cytotoxicity strongly increases when NK cells are stimulated by cytokines like IL-2, IL-15, IL-18, and many others. NK cell–mediated lysis of target cells is mainly mediated by the release of the cytotoxic molecules perforin and granzymes A and B. Cytokine production occurs on triggering of activating receptors (ARs), stimulation by cytokines present in the microenvironment, or both.

Cytotoxicity and cytokine production by NK cells contribute to innate immune responses and thus to the first line of defense of the organism before adaptive immunity develops. In addition, NK cells directly participate in the induction and regulation of adaptive immune responses: they stimulate maturation of dendritic cells (DCs),7, 8 eliminate immature DCs,7, 8 produce cytokines that influence CD4+ helper and CD8+ effector T cells,9, 10 and regulate T-cell activation and proliferation through direct cellular contacts.11, 12

NK cell inhibition and activation 

NK cell functions are governed by a balance between activating messages transmitted by their ARs and inhibitory signals transmitted by their inhibitory receptors (IRs).1, 13, 14 Inhibitory NK cell receptors specific for HLA class I molecules recognize either (1) restricted numbers of classical HLA class I alleles (mainly HLA-B and HLA-C alleles) in the case of killer immunoglobulin receptors (KIRs); (2) a broad panel of classical HLA class I molecules, as well as HLA-G, in the case of immunoglobulin-like transcript 2 (ILT2); and (3) the nonclassical MHC class I molecule HLA-E. This molecule presents peptides derived from the signal sequences of classical HLA class I molecules and is recognized by the C-type lectin heterodimer CD94/NKG2A.13, 14 The most potent ARs of NK cells are the antibody-dependent, cellular cytotoxicity–mediating molecule CD161; NKG2D1;15 and the natural cytotoxicity receptors NKp30, NKp44, and NKp46.16 The ligands of NKG2D are MHC class I chain–related proteins A and B (MICA and MICB) and retinoic acid early transcript 1, also called UL-16–binding proteins. These molecules are mostly absent from healthy cells but are induced on cellular stress, as in case of infection or malignant transformation.15 Viral proteins, such as hemagglutinins17, 18 and pp65 from human cytomegalovirus (CMV),19 have been suggested as ligands for natural cytotoxicity receptors. A ligand of NKp30 also seems to be expressed on human DCs because NK cell–mediated killing of immature DCs depends on NKp30 engagement.20 In addition, B7-H6, a member of the B7 family specifically expressed by human tumor cells but absent from normal cells, has been shown to be a ligand of NKp30.21

Healthy cells express normal amounts of HLA class I molecules and no or few ligands for major ARs. On encounter with an NK cell, an excess of inhibitory messages is transmitted to the NK cell through its IR, rendering an MHC class I–expressing target cell resistant to NK cell–mediated killing. This is in contrast to what is known about the effect of MHC on T cells: MHC (plus peptide) normally activates T-cell recognition and function. If the target cell becomes infected or malignant, it might lose expression of HLA class I molecules partially (weak NK cell inhibition) or totally (no NK cell inhibition), whereas stress-induced ligands for NK cell ARs are upregulated at the same time (strong activation). The balance in this case is in favor of activation, and the target will be killed by the NK cell.13, 14

It has recently become clear that only NK cells that express at least 1 IR (KIR or NKG2A) for a self-HLA class I molecule are functionally mature and are able to perform cytotoxicity and cytokine production, whereas those NK cells without such a receptor remain hyporesponsive. The first population is called “educated,” “licensed,” or “armed,” whereas the latter (up to 20% of all NK cells in peripheral blood) is called “unlicensed” or “disarmed”.22, 23, 24, 25

NK cell markers and subpopulations 

The relative expression of the NK cell markers CD16 and CD56 (a homotypic adhesion molecule) allows definition of several different NK cell subsets.6 In peripheral blood the numerically predominant population is CD56dimCD16bright (90% of all NK cells in healthy subjects). A maximum of 10% of NK cells belong to the CD56bright subset, which can be further subdivided into CD16− (30% to 50% of CD56bright cells) and CD16dim (50% to 70% of CD56bright cells) fractions.6

The 2 main peripheral blood NK cell subsets are quite different in terms of phenotype and function. CD56bright NK cells are less cytotoxic than CD56dim NK cells but produce many more cytokines and proliferate in response to picomolar concentrations of IL-2, which is due to their constitutive expression of the high-affinity IL-2 receptor. CD56bright NK cells express CD94/NKG2A at high levels but are mostly devoid of KIRs and ILT2. In contrast, KIRs and ILT2 are frequently found on subpopulations of CD56dim NK cells together with CD94/NKG2A. The repertoire of chemokine receptors and adhesion molecules is also very different between the 2 subsets, with CD56bright NK cells being equipped for migration to secondary lymphoid organs and sites of chronic inflammation, whereas CD56dim NK cells preferentially migrate to acute inflammatory sites. Accordingly, NK cells in lymph nodes are predominantly of the CD56bright type.6

For murine NK cells, most of the discussed aspects are the same. One exception is the fact that murine NK cell IRs are all of the C-type lectin superfamily (Ly49 and CD94/NKG2A) and not of the immunoglobulin superfamily, as in human subjects (KIR and ILT2). Murine Ly49 receptors are thus structurally different but functionally equivalent to human KIRs.26, 27

Cytokine production, antigen presentation, and memory 

NK1 and NK2 cells 

NK cells are an important source of IFN-γ, but they can also produce type 2 cytokines.1, 2, 3, 4, 5, 6 The former are called NK1 cells, by analogy with TH1 T cells, and have to be stimulated by type 1 cytokines, such as IL-12 (Table I).28 The combination of IL-12 and IL-18 is the most efficient stimulator of IFN-γ production by NK cells.29 NK2 cells arise after stimulation with the type 2 cytokine IL-4 and produce the type 2 cytokines IL-5 and IL-13.28 According to Loza et al,30 the cytokine production profile is closely related to the developmental stage of NK cells, with immature NK cells producing type 2 cytokines and mature NK cells producing type 1 cytokines.

Table I. NK cell subsets according to their cytokine production profile
NK subsetLocalizationInducing cytokinesCytokines producedReferences
NK1PB, LNIL-12/IL-18IFN-γ/TNF-α28, 29, 30
NK2PB, LNIL-4IL-5/IL-1328, 29, 30
NK3 or NKregPB, LNIL-2;?IL-10/TGF-β31, 32, 33, 34, 35, 36, 37, 38, 39
NK-22Skin, tonsils, gut mucosaIL-23IL-2240

LN, Lymph nodes; NKreg, NK regulatory cell; PB, peripheral blood.

NK regulatory cells 

TGF-β– and IL-10–producing NK3-like cells have also been described.31 This has led to the concept of the NK regulatory cell. Some authors consider all NK cells to be regulatory because they influence innate and adaptive immune responses. By analogy with regulatory T cells, however, it would be better to limit this designation only to those NK cells that indeed suppress other immune cells. Several recent articles nicely describe this phenomenon, which is in most cases due to IL-10 secretion by NK cells but can also rely on the killing of, for example, regulatory T cells.32, 33, 34, 35, 36, 37, 38, 39

NK-22 cells 

Most recently, mucosa-associated IL-22–producing NK cells have been discovered and are called NK-22 cells.40 IL-22 is a cytokine that protects the epithelial cell barrier, notably in the gut and the skin, from pathogens, which can have both proinflammatory and anti-inflammatory capacities (depending on the inflammatory context). This molecule is also secreted by TH17 T cells, natural killer T (NKT) cells, and γδ T cells.40, 41 Interestingly, NK-22 cells do not produce IL-17,40 although conventional NK cells are able to release this cytokine.42, 43 (the best studied IL-17–producing cells are the proinflammatory TH17 T lymphocytes, the pathogenic role of which in psoriasis and atopic dermatitis [AD] is well known44).

Antigen presentation 

NK cells have also been described as being equipped with the potential to process and present antigens to T cells. On activation, NK cells express HLA class II molecules and several ligands for T-cell costimulatory receptors (CD80, CD86, CD70, and OX40 ligand). Under these conditions, NK cells are able to stimulate the proliferation of antigen-specific T cells, although not as efficiently as professional antigen-presenting cells, such as DCs.45

NK cells and memory 

A very recent finding in the mouse that has yet to be confirmed in human subjects is the existence of memory NK cells. The work on a murine model of hapten-induced contact hypersensitivity (CHS) by O'Leary et al46 was historically the first to describe “adaptive,” memory-like NK cell responses. Mice devoid of T and B cells were able to mount CHS responses, which persisted for several weeks and were hapten specific. CHS could be transferred by NK cells from sensitized mice to naive recipients.46 The molecular mechanism of these recall responses is not known.

After infection of the animals with murine CMV, Ly49H+ (an NK cell AR involved in the recognition of a CMV-encoded protein) NK cells selectively proliferate and persist in the host for several months. On reinfection, they respond faster and stronger in terms of cytotoxicity and cytokine production than naive NK cells. Transfer of these adaptive NK cells into naive hosts results in further expansion and protective immunity.47 Memory-like NK cells in the mouse have likewise been described by Cooper et al.48

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NK cells and AD 

AD is a pruritic, relapsing, and often chronic skin inflammation, the prevalence of which has doubled or tripled over the last 3 decades. It affects up to 30% of children and up to 10% of adults in industrialized countries.49 These subjects often have a family background of other atopic diseases, such as allergic keratoconjunctivitis, allergic rhinitis, and allergic asthma. The disease has a strong hereditary component and arises from complex gene-gene and gene-environment interactions. The key defects in AD are related to a disrupted epithelial barrier function caused by loss-of-function mutations in the filaggrin gene and dysfunctions in both the adaptive and innate immune system.50, 51

Acute phase of AD and TH2 and TH17 cells 

In the past, adaptive immune defects have been intensively investigated, showing the inherited dominance of TH2 responses in atopic subjects.52 It has been shown that during the acute phases of AD, normally innocuous proteins trigger the production of IL-4, IL-5, and IL-13, which leads to IgE secretion from plasma cells and eosinophil activation in sensitized subjects.53 Although such a link is commonly accepted only in patients with psoriasis and is controversially discussed in patients with AD, there might be a potential involvement of TH17 cells in patients with AD, especially during its onset.54, 55 It has been shown by means of immunohistochemistry that IL-17+ cells are increased in numbers in acute, but not in chronic, AD lesions compared with numbers seen in unaffected skin.56

Chronic phase of AD (TH0 cells, TH1 cells, inflammatory dendritic epidermal cells, and TH22 cells) 

In the chronic phase of eczema, TH0 cells (cells that share activities of both TH1 and TH2 cells) and TH1 cells are predominant, and the concentration of the TH1 cytokine IFN-γ increases locally and systemically.57 This is followed by a peak of IL-12 expression that coincides with the appearance of inflammatory dendritic epidermal cells (IDECs) in the skin.58 The IDEC subset, which can be distinguished from Langerhans cells (LC) by its expression of the macrophage mannose receptor CD206, is predominant in chronic AD skin lesions and is even present in the mild residual infiltrate in normal-looking skin between flares.59, 60 By producing IL-12 and IL-18 and by releasing proinflammatory cytokines, IDECs seem to contribute to the chronification of the eczema. The genetically inherited barrier dysfunction together with the enhanced expression of the high-affinity receptor for IgE, FcεRI, on LCs and IDECs in the epidermis of lesional atopic skin facilitates allergen uptake, allergen binding, and IgE sensitization.61, 62, 63 Recently, a different subset of T cells with skin-homing potential, which produces IL-22 but not IL-17 or IFN-γ (ie, the so-called TH22 cells) has been identified and seems to accumulate in chronic AD lesions.43, 54, 64, 65 In the skin IL-22 mediates keratinocyte proliferation and epidermal acanthosis and might account for the lichenification seen in chronic AD skin lesions.66

AD and NK cell subsets (NK2, NK-22, and lymphoid tissue inducer–like cells) 

Over the last few years, numerous innate immune defects important for defense at the interface between epithelial cells and the environment have been described in patients with AD. These innate immune defects can promote inflammation and therefore aggravate or even trigger the development of AD. Atopic subjects are specifically susceptible to cutaneous staphylococcal, streptococcal, and herpes simplex virus infections. This is due to the inflammatory TH2-biased micromilieu that leads to functional impairment of Toll-like receptor–mediated activation of epithelial cells and that reduces the production of antimicrobial peptides locally.67, 68, 69 Reports have shown that TH17 cells, with their propensity to produce IL-17 and IL-22, are essential for first-line defense against several fungal and bacterial infections.70 A severely impaired IL-17–mediated immune response can lead to recurrent and persistent infections of the skin and mucosal membranes, as seen in patients with chronic mucocutaneous candidiasis.71 The relative deficiency of IL-17 found in chronic AD skin lesions might add to the reduced efficiency of innate defense molecules to skin-tropic pathogens.54

Very recently, 2 distinct NK cell populations have been identified in human skin, as well as in the intestine (Peyer patches), mucosal-associated lymphoid tissue, and tonsils, which have the capacity to produce either IL-22 or both IL-22 and IL-17 and are therefore prime candidates for constituting a link to skin pathophysiologies, such as AD and psoriasis. NK-22 cells are a special subset of NKp46+ NK cells with a diminished capacity to degranulate and produce IFN-γ.72, 73 Instead, NK-22 cells express the nuclear hormone receptor retinoic acid receptor-related orphan receptor γ t and produce large amounts of IL-22 in response to IL-23, which serves to induce the production of antimicrobial molecules in epithelial tissues.74 The other subset, referred to as human lymphoid tissue inducer (LTi)–like cells, is a committed NK cell precursor population that was shown to initiate lymph node organogenesis during embryogenesis and that probably gives rise to the NK-22 cell. LTi-like cells are able to produce both IL-17 and IL-22 after stimulation in vitro.23, 75 It is a plausible hypothesis that NK-22 cells and LTi-like cells, given this cytokine profile and their location in these distinct anatomic sites, contribute to those specific inflammatory skin disorders that are characterized by the contribution from IL-17 and IL-22.

Histologically, atopic skin lesions are not only characterized by the well-described infiltrate of CD4+ and, to a lesser extent, CD8+ T lymphocytes, FcεRI+ LCs, and FcεRI+ IDECs, CD56+ NK cells are also present in the epidermis and even more in the dermal atopic infiltrate.76, 77 Recent studies have shown that patients with AD harbor an increased frequency of L-selectin–positive CD16+ NK cells in the peripheral blood compared with that seen in healthy control subjects.78 In addition, increased levels of the NK cell chemoattractants monocyte chemoattractant protein 1/CCL2 and macrophage-derived chemokine/CCL22, which are derived from keratinocytes and CD1a+ DCs, are expressed in lesional skin of patients with AD (Table II).76, 79, 80 In accordance with these findings, in Malassezia species atopy patch test–positive skin, where the yeast Malassezia species acts as an allergen in the skin of patients with AD, numerous CD3−CD56+ NK cells have been found in the dermal lesions.76 These NK cells were in close contact with CD1a+ DCs. In vitro Malassezia species can be taken up by immature monocyte-derived DCs, leading to their maturation and to the production of cytokines with the potential to skew the immune outcome toward a TH2-like response. The DCs pretreated with Malassezia species showed a reduced susceptibility to NK cell–induced cell death and might therefore have an increased capacity to sustain the atopic inflammation.

Table II. Findings about NK cells in various skin diseases
DiseaseFindings on NK cellsReferences
Atopic dermatitis, humanLesional skin: CCL2 and CCL22 (NK cell chemoattractant) levels increased76, 79, 80
PB: activated NK cells, more NK2 cells86
Atopic dermatitis, murineEczema vaccinatum: impaired NK cell activity77
Psoriasis, humanLesional skin: 5% to 8% NK cells (CD56brightCD16−)107
NK cells from lesional skin: high IFN-γ and TNF-α production107
NK cells from lesional skin: expression of chemokine receptors CXCR3 and CCR5107
Lower number of NK cells in PB: accumulation at sites of inflammation?108
Alopecia areata, humanBreakdown of immunoprivilege, increased NK cell activity121
Lesional IFN-γ levels increased, NKG2D expression increased on lesional NK cells121
Lesional MICA expression increased, lesional MIF expression increased122
PB: NKG2C and NKG2D expression increased, KIR expression decreased122, 124
Pemphigus vulgaris, humanPB: increased NK cell numbers125
Activated state125, 126
Decreased responses to TH1 cytokines125
Higher expression of IL-5125
Antigen presentation?126

PB, Peripheral blood.

Reported results regarding the potential role of NK cells in patients with AD are complex but compatible with a common interpretation at closer inspection.81, 82 The main focus has been the number of NK cells in peripheral blood and their level of activation. In patients with AD, a numeric decrease of NK cells in the periphery has been most consistently reported.81, 83 NK cells leaving the circulation and accumulating in tissues could account for the lower number of NK cells reported in these studies. This shift of NK cells to the site of allergic inflammation was also evident in earlier studies in animal models of allergic asthma84 or allergic peritonitis.85 In human vernal keratoconjunctivitis, a complex type I–mediated hypersensitivity reaction of the conjunctiva also involving IgE-independent pathogenic mechanisms, NK cells constitute a significant proportion of the immune cells infiltrating the conjunctiva.86 Here again, concomitant with the accumulation of NK cells at the site of allergic infiltration, a decrease in circulating NK cell numbers in the blood was observed. The transient increase of NK cell numbers in the blood of patients with AD shortly after stress exposure (up to 1 hour) underlines the potential immunologic relevance of these cells, especially if the IFN-γ production by NK cells is considered.87

The alterations in cytokine production by NK cells in patients with AD has been studied, with somewhat contradictory results. One group found that patients with AD harbored highly activated NK cells in vivo, as indicated by a high spontaneous release of IL-4, IL-5, IL-13, and IFN-γ from isolated lesional NK cells.88 Analogous to the enhanced polarization toward TH2 cells and their cytokines in early AD lesions, as outlined above, the percentages of IL-5– and IL-13–producing NK cells were significantly higher in patients with AD than in healthy subjects in the same study. On the other hand, several groups have reported a significantly lower production of TNF-α and IFN-γ from NK cells at a single-cell level in patients with AD.89, 90 An imbalance between TH1 and TH2 cells from early infancy on (ie, an inherent reduction in IFN-γ production from TH1 cells but also from NK cells) has been found consistently in childhood AD.81, 83 This is thought to shift the subsequent adaptive immune responses toward a type 2 response, thereby promoting allergy and infection.

In general, changes in NK cell numbers have to be interpreted with some caution because of the rapid redistribution of these cells.91, 92 In addition, differing experimental outcomes can also result from variations in disease parameters, such as activity, chronicity, and treatment modalities, and do not necessarily indicate NK cells as a key prerequisite for AD pathogenicity.

The most reliable evidence for an impaired activity of NK cells in atopic lesional skin comes from a murine model of eczema vaccinatum, a disseminated vaccinia infection resulting from smallpox vaccination of subjects or animals with AD.77 In the murine model it is the production of IL-17A and probably other TH17-related cytokines in the inflamed atopic skin that reduces the ability of NK cells to kill virus-infected cells. This leads to viral spreading, with an increased susceptibility of mice with AD to experience eczema vaccinatum.

In summary, several NK cell subsets are present and implicated in the different stages of AD and AD-associated cutaneous infections.

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NK cells and psoriasis 

Psoriasis is a genetically determined, autoinflammatory, chronic relapsing skin disorder without involvement of known infectious agents or antigens.93, 94 Clinically, the disease is characterized by scaly and raised erythematous plaques. An imbalance between steady-state levels of environmental and genetic factors induced by, for example, bacterial products initiates the inflammatory process. So-called inflammatory dermal DCs (CD11c+CD1c–) that secrete TNF-α and produce inducible nitric oxide synthase (Tip-DCs) are of major pathophysiologic relevance for psoriatic inflammation.95 Effective treatment of psoriasis downmodulates Tip-DC products, such as TNF-α–inducible nitric oxide synthase, IL-20, and IL-23.95 Because of their production of IL-23, Tip-DCs are also able to stimulate the differentiation and activation of TH17 cells.95 During disease progression, activated myeloid DCs migrate to the draining lymph nodes, present autoantigens to T cells, and lead further to the differentiation of TH17 cells, type 17 cytotoxic T (TC17) cells, and TH1 or type 1 cytotoxic T (TC1) cells.93 The production of IL-17A and IL-17F by TH17 and TC17 cells upregulates the expression of specific chemokines (eg, CXCL1, CXCL9 to CXCL11, and CCL20) that are increased in psoriatic lesions. IL-22 from TH17 cells downregulates keratinocyte differentiation genes and is involved in keratinocyte hyperplasia.66, 96 Both IL-17 and IL-22 induce the synthesis of antimicrobial peptides (eg, cathelicidin and β-defensins) from various epithelial cell types in human subjects, including keratinocytes, suggesting their participation in host defense.23, 97, 98, 99, 100 IFN-γ and TNF-α produced by TH1 and TC1 cells are largely proinflammatory mediators in patients with psoriasis, leading to the activation and proliferation of antigen-presenting cells and keratinocytes.101 The importance of TNF-α is stressed by the clinical success of an anti–TNF-α therapy in psoriasis treatment.102

More recently, intrinsic cutaneous factors have been shown to predispose skin to psoriasis development, requiring the innate immune system.103, 104 Autologous human lymphocytes with NK cell receptors (NK and NKT cells), when injected into nonlesional skin grafts from psoriatic patients on mice with severe combined immunodeficiency, caused the classic pathology of psoriasis, such as epidermal thickness, proliferation, and expression of epidermal HLA-DR, intercellular adhesion molecule 1, CD1d, and K-16.105 NKT cells are a subset of lymphocytes that express T-cell receptors and NK cell receptors, such as CD94 and CD161. NKT cells (CD3+CD56+) are thought to belong to the innate immune system and seem to play an important role in psoriasis by recognizing glycolipids through CD1d-expressing keratinocytes, thereby activating IFN-γ–producing or self-reactive lymphocytes.106 In lesional psoriatic skin, about 5% to 8% of CD3−CD56+ true NK cells are located to the mid and papillary dermis.107 These NK cells mostly belong (up to 80%) to the immunoregulatory CD56brightCD16− NK subtype that is recruited from the about 5% to 10% circulating NK cells that home to secondary lymphoid organs and modulate adaptive immune responses.107 When isolated, NK cells from lesional psoriatic skin produce high amounts of IFN-γ and (although to a lesser extent) TNF-α. It has been speculated that immigrating papillary DCs activate these NK cells, leading to the release of high amounts of type 1 cytokines, which then polarize T cells toward the TH1 type. Psoriatic NK cell supernatants are potent in inducing intercellular adhesion molecule 1 and MHC class II expression on cultured psoriatic keratinocytes and can promote the release of the chemoattractants CXCL10, CCL5, and CCL20 by keratinocytes.107 CD56brightCD16− NK cells from psoriatic skin express the chemokine receptors CXCR3 and CCR5 and bind to keratinocyte-derived CXCL10 and CCL5, leading to their accumulation in inflamed skin. Such findings are very significant because they are about NK cells isolated directly from diseased skin. The number of NK cells in the peripheral blood of patients with psoriasis has been found to be decreased, but levels of T cells, activated T cells, and NKT cells are normal.108 This constellation can be also found in other autoinflammatory-related disorders, such as lupus erythematosus.109, 110 There seems to be evidence that NK cell depletion can lead to a TH1 cytokine bias and that NK cells regulate autoimmunity.111 However, as already outlined, assessment of peripheral blood NK cell counts is of questionable significance and therefore of limited value because of the rapid redistribution of these cells.91, 92

In conclusion, these results can be considered strong evidence of an active participation of NK cells in psoriasis development.

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NK cells and alopecia areata 

Alopecia areata (AA) is an inflammatory, often reversible hair loss affecting mainly children and young adults. Clinically, round hairless patches appear on the scalp while hair follicles remain intact. Normally, in the distal part of the human hair follicle immune system, interacting intraepithelial T cells and LCs build up an effective defense strategy. During the growth stage of the hair cycle (anagen phase), hair follicles belong to the few immunoprivileged sites in the mammalian body.112 A collapse of the immune privilege (IP) of the hair follicle results in the loss of hair, as seen in patients with AA.113, 114 The cause of this collapse is, however, diverse and seems to involve T cell–mediated immunologic changes, neuropeptides, genetic disposition to autoimmunity, and distress.115 Histologically, the disease is characterized by an abundance of catagen follicles in lesional skin and the presence of intrafollicular and perifollicular inflammatory cell infiltrates consisting of many CD4+ and even more CD8+ T lymphocytes, mast cells, macrophages, and LCs that target hair follicle keratinocytes, melanocytes, and dermal papillary fibroblasts.116

Like other sites of IP, such as the proximal nail matrix (PNM) or the fetomaternal placental unit, the hair follicle area is characterized by low HLA class I expression; reduced capacity of antigen presentation; expression of local immunosuppressants, such as TGF-β and IL-10 from regulatory T cells; and inhibition of NK cell activities.117, 118, 119 It might be expected that the absence or low expression of HLA class I in these immunoprivileged sites would allow for NK cell activation because NK cells attack cells with low or absent HLA class I expression, but this is clearly not the case. For example, compared with other regions of the nail epithelium, the PNM contains keratinocytes and melanocytes with significantly downregulated MHC class I expression, whereas HLA-G expression is upregulated. This upregulation, together with the NK-suppressing macrophage migration inhibitory factor (MIF) expressed in PNM, likely serves to inhibit NK cell attack on MHC class I–negative PNM.118 In addition, in the placenta human uterine NK cells remain tolerant at the maternal-fetal interface, probably because of the production of vascular endothelial growth factor. This proangiogenic factor is produced by the uterine NK cells themselves and decreases their cytotoxic activity.119

Multiple samples from normal human scalp show that there is no NK cell attack on normal, HLA-low anagen hair follicles.120 In AA lesions CD4+ and CD8+ T cells are clustered at a high density around the anagen hair bulb. In addition, many perifollicular CD56+ NK cells with high expression of the NK cell AR NKG2D are present in atrophic AA lesions but not in normal scalp or scalp from patients with AD.121 At the same time, the ligand for NKG2D, MICA, was found to be expressed at very high levels in the proximal outer root sheath, the dermal papilla, and the connective tissue sheath of AA hair follicles.122 This suggests that the upregulation of MICA in lesional AA enhances the susceptibility of these hair follicles for an attack by NKG2D+ NK cells, which can then promote anagen termination and AA progression. IFN-γ is now appreciated as a key cytokine in the pathogenesis of AA, presumably by mediating the collapse of the IP of anagen hair follicles.123 IFN-γ is able to upregulate NKG2D on normal NK cells,122 which suggests that this is the reason for the increased expression of the AR NKG2D on NK cells from patients with AA. In peripheral blood NK cells of patients with AA express increased levels of the NK cell ARs NKG2D and NKG2C and reduced expression of the NK IR KIR-2DL2/2DL3 compared with that seen in healthy control subjects or patients with other inflammatory diseases.122, 124 This suggests that NK cells in patients with AA are considerably more responsive to activating stimuli than those in healthy control subjects. In addition to NK cell receptors and their ligands, MIF, which is normally present in IP areas and can potently suppress NK cell activity, is also aberrantly expressed in lesional AA.122 Whereas normal anagen hair follicles show widespread MIF expression throughout most of the epithelium of normal anagen scalp hair follicles, epithelium of lesional skin AA hair follicles displays reduced or absent MIF expression. Hair follicles in patients with AA might therefore have a decreased capacity to suppress undesired NK cell activity.

In conclusion, as in other IP sites of the human body, the level of NK cell activity in the hair follicle seems to be an important parameter to establish an immunosuppressive environment, a condition that seems to be altered in patients with AA.

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NK cells and pemphigus vulgaris 

Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucous membranes.125 It is mediated by anti–desmoglein 3 autoantibodies capable of directly causing acantholysis in the epidermis.125, 126

One study found average NK cell values from patients with PV to be similar to those of healthy donors.127 In contrast, Takahashi et al125 described a significantly higher percentage and absolute number of NK cells (among total peripheral blood lymphocytes) in patients with PV compared with those seen in healthy control subjects. Moreover, a large fraction of these cells are activated, as demonstrated by the expression of CD69. Although not different in terms of cytotoxic activity, NK cells from patients with PV show reduced levels of mRNA for the IL-12 receptor β2, perforin, and granzyme B, as well as impaired IL-12 signaling.125 In the same study IL-10 production was reduced, but IL-5 mRNA was present in NK cells from patients with active disease.125 A possible caveat of these studies is that they explored peripheral blood NK cells, which might not necessarily reflect the situation in the diseased skin.

Stern et al126 confirm the activation state of at least a fraction of NK cells from patients with PV expressing ex vivo HLA-DR and the costimulatory molecule B7-H3. On coculture of NK cells with autologous CD4+ T cells in the presence of desmoglein 3 peptides, T cells proliferated, suggesting that NK cells from patients with PV can function as antigen-presenting cells. However, no data supporting antigen uptake and processing by NK cells are provided in this article. Thus the exogenous peptides might have bound “externally” to the HLA-DR molecules expressed by NK cells without any processing by the latter. The supernatant of cocultures from patients with active PV contained high levels of IL-6, IL-8, and IFN-γ, which might indicate that the NK cells stimulated the T cells to produce these cytokines, although patients' NK cells are able to produce the same cytokines.126

Overall, peripheral blood NK cells seem to be activated in patients with PV and might contribute to the pathogenesis of the disease by promoting TH2 responses,126 inflammatory cytokine production,125 or both. Evidence for an antigen-presenting role of NK cells in patients with PV seems weak and thus requires more investigation.

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Conclusion 

Initially seen merely as primitive killers, NK cells have in recent years been increasingly recognized as a group of immune cells that actively participate in the regulation of both innate and adaptive immunity. Given this physiologic role, it is hardly surprising that NK cells also contribute to pathophysiologic situations of immune deviation.

In skin diseases the role of NK cells is just beginning to be understood. There is, however, good evidence that NK cells contribute in particular to those diseases that are, at least in part, determined by IL-22 and IL-17. Future work will no doubt delineate the contribution of NK cells and their subpopulations to the pathogenesis of AD and psoriasis. Increased NK cell activities constitute key features in the breakdown of areas of relative IP, such as the anagen hair bulb epithelium or the PNM. The restoration of the IP collapse by downregulating the IFN-γ–driven inflammation might be an effective future strategy for the treatment of AA. The involvement of NK cells in patients with PV needs to be confirmed, especially with respect to the question of whether NK cell dysfunctions in the periphery are the cause or consequence of the disease.

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 Supported by grants from the Ministry of Culture, Higher Education, and Research (MCESR), Luxembourg, and the National Research Fund (FNR), Luxembourg.

 Disclosure of potential conflict of interest: F. Hentges receives research support from Fonds National de la Recherche. J. Zimmer receives research support from Ministry of Research (Luxembourg) and Fonds National de la Recherche (Luxembourg). All other authors declare no conflicts of interest.

PII: S0091-6749(09)01737-0

doi:10.1016/j.jaci.2009.11.020

The Journal of Allergy and Clinical Immunology
Volume 125, Issue 1 , Pages 60-68, January 2010