Natural killer cells in atopic and autoimmune diseases of the skin

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. 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. 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.1Smyth M.J. Hayakawa Y. Takeda K. Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer.Nat Rev Immunol. 2002; 2: 850-861Google Scholar, 2Carayannopoulos L.N. Yokoyama W.M. Recognition of infected cells by natural killer cells.Curr Opin Immunol. 2004; 16: 26-33Crossref PubMed Scopus (44) Google Scholar, 3Vivier E. Tomasello E. Baratin M. Walzer T. Ugolini S. Functions of natural killer cells.Nat Immunol. 2008; 9: 503-510Crossref PubMed Scopus (692) Google Scholar, 4Caligiuri M.A. Human natural killer cells.Blood. 2008; 112: 461-469Crossref PubMed Scopus (479) Google Scholar, 5Cooper M.A. Colonna M. Yokoyama W.M. Hidden talents of natural killers: NK cells in innate and adaptive immunity.EMBO Rep. 2009; 10: 1103-1110Crossref PubMed Scopus (50) Google Scholar, 6Poli A. Michel T. Thérésine M. Andrès E. Hentges F. Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset.Immunology. 2009; 126: 458-465Crossref PubMed Scopus (102) Google Scholar 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),7Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues.Nat Rev Immunol. 2002; 2: 957-964Crossref PubMed Scopus (428) Google Scholar, 8Degli-Esposti M.A. Smyth M.J. Close encounters of different kinds: dendritic cells and NK cells take center stage.Nat Rev Immunol. 2005; 5: 112-124Crossref PubMed Scopus (321) Google Scholar eliminate immature DCs,7Moretta A. Natural killer cells and dendritic cells: rendezvous in abused tissues.Nat Rev Immunol. 2002; 2: 957-964Crossref PubMed Scopus (428) Google Scholar, 8Degli-Esposti M.A. Smyth M.J. Close encounters of different kinds: dendritic cells and NK cells take center stage.Nat Rev Immunol. 2005; 5: 112-124Crossref PubMed Scopus (321) Google Scholar produce cytokines that influence CD4+ helper and CD8+ effector T cells,9Yokoyama W.M. Kim S. French A.R. The dynamic life of natural killer cells.Ann Rev Immunol. 2004; 22: 405-429Crossref PubMed Scopus (305) Google Scholar, 10Martin-Fontecha A. Thomsen L.L. Brett S. Gerard C. Lipp M. Lanzavecchia A. et al.Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming.Nat Immunol. 2004; 5: 1260-1265Crossref PubMed Scopus (621) Google Scholar and regulate T-cell activation and proliferation through direct cellular contacts.11Assarsson E. Kambayashi T. Schatzle J.D. Cramer S.O. von Bonin A. Jensen P. et al.NK cells stimulate proliferation of T and NK cells through 2B4/CD48 interactions.J Immunol. 2004; 173: 174-180Crossref PubMed Google Scholar, 12Zingoni A. Sornasse T. Cooks B.G. Tanaka Y. Santoni A. Lanier L.L. Cross-talk between activated human NK cells and CD4+ T cells via OX40-OX40 ligand interactions.J Immunol. 2004; 173: 3716-3724Crossref PubMed Google Scholar NK cell functions are governed by a balance between activating messages transmitted by their ARs and inhibitory signals transmitted by their inhibitory receptors (IRs).1Smyth M.J. Hayakawa Y. Takeda K. Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer.Nat Rev Immunol. 2002; 2: 850-861Google Scholar, 13Lanier L.L. NK cell recognition.Annu Rev Immunol. 2005; 23: 2225-2274Crossref Scopus (1381) Google Scholar, 14O'Connor G.M. Hart O.M. Gardiner C.M. Putting the natural killer cell in its place.Immunology. 2006; 117: 1-10Crossref PubMed Scopus (88) Google Scholar 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.13Lanier L.L. NK cell recognition.Annu Rev Immunol. 2005; 23: 2225-2274Crossref Scopus (1381) Google Scholar, 14O'Connor G.M. Hart O.M. Gardiner C.M. Putting the natural killer cell in its place.Immunology. 2006; 117: 1-10Crossref PubMed Scopus (88) Google Scholar The most potent ARs of NK cells are the antibody-dependent, cellular cytotoxicity–mediating molecule CD161; NKG2D1;15Raulet D.H. Roles of the NKG2D immunoreceptor and its ligands.Nat Rev Immunol. 2003; 3: 781-790Crossref PubMed Google Scholar and the natural cytotoxicity receptors NKp30, NKp44, and NKp46.16Moretta A. Bottino C. Vitale M. Pende D. Cantoni C. Mingari M.C. et al.Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis.Annu Rev Immunol. 2001; 19: 197-233Crossref PubMed Scopus (1010) Google Scholar 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.15Raulet D.H. Roles of the NKG2D immunoreceptor and its ligands.Nat Rev Immunol. 2003; 3: 781-790Crossref PubMed Google Scholar Viral proteins, such as hemagglutinins17Mandelboim O. Lieberman N. Lev M. Paul T. Arnon T.I. Bushkin Y. et al.Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells.Nature. 2001; 409: 1055-1060Crossref PubMed Scopus (500) Google Scholar, 18Arnon T.I. Lev M. Katz G. Chernobrov Y. Porgador A. Mandelboim O. Recognition of viral hemagglutinins by NKp44 but not NKp30.Eur J Immunol. 2001; 31: 2680-2689Crossref PubMed Scopus (220) Google Scholar and pp65 from human cytomegalovirus (CMV),19Arnon T.I. Achdout H. Levi O. Merkel G. Saleh N. Katz G. et al.Inhibition of the NKp30 activating receptor by pp65 from human cytomegalovirus.Nat Immunol. 2005; 6: 515-523Crossref PubMed Scopus (197) Google Scholar 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.20Ferlazzo G. Tsang M.L. Moretta L. Melioli G. Steinman R.M. Münz C. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells.J Exp Med. 2002; 195: 343-351Crossref PubMed Scopus (624) Google Scholar 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 NKp30.21Brandt C.S. Baratin M. Yi E.C. Kennedy J. Gao Z. Fox B. et al.The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans.J Exp Med. 2009; 206: 1495-1503Crossref PubMed Scopus (176) Google Scholar 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.13Lanier L.L. NK cell recognition.Annu Rev Immunol. 2005; 23: 2225-2274Crossref Scopus (1381) Google Scholar, 14O'Connor G.M. Hart O.M. Gardiner C.M. Putting the natural killer cell in its place.Immunology. 2006; 117: 1-10Crossref PubMed Scopus (88) Google Scholar 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”.22Fernandez N.C. Treiner E. Vance R.E. Jamieson A.M. Lemieux S. Raulet D.H. A subset of natural killer cells achieves self-tolerance without expressing inhibitory receptors for self-MHC molecules.Blood. 2005; 105: 4416-4423Crossref PubMed Scopus (287) Google Scholar, 23Kim S. Poursine-Laurent J. Truscott S.M. Lybarger L. Song Y.J. Yang L. et al.Licensing of natural killer cells by host major histocompatibility complex class I molecules.Nature. 2005; 436: 709-714Crossref PubMed Scopus (503) Google Scholar, 24Raulet D.H. Vance R.E. Self-tolerance of natural killer cells.Nat Rev Immunol. 2006; 6: 520-531Crossref PubMed Scopus (240) Google Scholar, 25Anfossi N. André P. Guia S. Falk C.S. Roetynck S. Stewart C.A. et al.Human NK cell education by inhibitory receptors for MHC class I.Immunity. 2006; 25: 331-342Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar The relative expression of the NK cell markers CD16 and CD56 (a homotypic adhesion molecule) allows definition of several different NK cell subsets.6Poli A. Michel T. Thérésine M. Andrès E. Hentges F. Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset.Immunology. 2009; 126: 458-465Crossref PubMed Scopus (102) Google Scholar 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.6Poli A. Michel T. Thérésine M. Andrès E. Hentges F. Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset.Immunology. 2009; 126: 458-465Crossref PubMed Scopus (102) Google Scholar 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.6Poli A. Michel T. Thérésine M. Andrès E. Hentges F. Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset.Immunology. 2009; 126: 458-465Crossref PubMed Scopus (102) Google Scholar 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.26Anderson S.K. Ortaldo J.R. McVicar D.W. The ever-expanding Ly49 gene family: repertoire and signaling.Immunol Rev. 2001; 181: 79-89Crossref PubMed Scopus (93) Google Scholar, 27Kane K.P. Silver E.T. Hazes B. Specificity and function of activating Ly-49 receptors.Immunol Rev. 2001; 181: 104-114Crossref PubMed Scopus (46) Google Scholar NK cells are an important source of IFN-γ, but they can also produce type 2 cytokines.1Smyth M.J. Hayakawa Y. Takeda K. Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer.Nat Rev Immunol. 2002; 2: 850-861Google Scholar, 2Carayannopoulos L.N. Yokoyama W.M. Recognition of infected cells by natural killer cells.Curr Opin Immunol. 2004; 16: 26-33Crossref PubMed Scopus (44) Google Scholar, 3Vivier E. Tomasello E. Baratin M. Walzer T. Ugolini S. Functions of natural killer cells.Nat Immunol. 2008; 9: 503-510Crossref PubMed Scopus (692) Google Scholar, 4Caligiuri M.A. Human natural killer cells.Blood. 2008; 112: 461-469Crossref PubMed Scopus (479) Google Scholar, 5Cooper M.A. Colonna M. Yokoyama W.M. Hidden talents of natural killers: NK cells in innate and adaptive immunity.EMBO Rep. 2009; 10: 1103-1110Crossref PubMed Scopus (50) Google Scholar, 6Poli A. Michel T. Thérésine M. Andrès E. Hentges F. Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset.Immunology. 2009; 126: 458-465Crossref PubMed Scopus (102) Google Scholar 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) .28Perritt D. Robertson S. Gri G. Showe L. Aste-Amezaga M. Trinchieri G. Cutting edge: Differentiation of human NK cells into NK1 and NK2 subsets.J Immunol. 1998; 161: 5821-5824PubMed Google Scholar The combination of IL-12 and IL-18 is the most efficient stimulator of IFN-γ production by NK cells.29Fehniger T.A. Shah M.H. Turner M.J. Vandeusen J.B. Whitman S.P. Cooper M.A. et al.Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.J Immunol. 1999; 162: 4511-4520PubMed Google Scholar NK2 cells arise after stimulation with the type 2 cytokine IL-4 and produce the type 2 cytokines IL-5 and IL-13.28Perritt D. Robertson S. Gri G. Showe L. Aste-Amezaga M. Trinchieri G. Cutting edge: Differentiation of human NK cells into NK1 and NK2 subsets.J Immunol. 1998; 161: 5821-5824PubMed Google Scholar According to Loza et al,30Loza M.J. Zamai L. Azzoni L. Rosati E. Perussia B. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells.Blood. 2002; 99: 1273-1281Crossref PubMed Scopus (80) Google Scholar 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 INK cell subsets according to their cytokine production profileNK subsetLocalizationInducing cytokinesCytokines producedReferencesNK1PB, LNIL-12/IL-18IFN-γ/TNF-α28Perritt D. Robertson S. Gri G. Showe L. Aste-Amezaga M. Trinchieri G. Cutting edge: Differentiation of human NK cells into NK1 and NK2 subsets.J Immunol. 1998; 161: 5821-5824PubMed Google Scholar, 29Fehniger T.A. Shah M.H. Turner M.J. Vandeusen J.B. Whitman S.P. Cooper M.A. et al.Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.J Immunol. 1999; 162: 4511-4520PubMed Google Scholar, 30Loza M.J. Zamai L. Azzoni L. Rosati E. Perussia B. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells.Blood. 2002; 99: 1273-1281Crossref PubMed Scopus (80) Google ScholarNK2PB, LNIL-4IL-5/IL-1328Perritt D. Robertson S. Gri G. Showe L. Aste-Amezaga M. Trinchieri G. Cutting edge: Differentiation of human NK cells into NK1 and NK2 subsets.J Immunol. 1998; 161: 5821-5824PubMed Google Scholar, 29Fehniger T.A. Shah M.H. Turner M.J. Vandeusen J.B. Whitman S.P. Cooper M.A. et al.Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.J Immunol. 1999; 162: 4511-4520PubMed Google Scholar, 30Loza M.J. Zamai L. Azzoni L. Rosati E. Perussia B. Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells.Blood. 2002; 99: 1273-1281Crossref PubMed Scopus (80) Google ScholarNK3 or NKregPB, LNIL-2;?IL-10/TGF-β31Zhou R. Wei H. Tian Z. NK3-like NK cells are involved in protective effect of polyinosinic-polycytidylic acid on type 1 diabetes in nonobese diabetic mice.J Immunol. 2007; 178: 2141-2147Crossref PubMed Google Scholar, 32Zhang C. Zhang J. Tian Z. The regulatory effect of natural killer cells: do “NK-reg cells” exist?.Cell Mol Immunol. 2006; 3: 241-254PubMed Google Scholar, 33Brillard E. Pallandre J.R. Chalmers D. Ryffel B. Radlovic A. Seilles E. et al.Natural killer cells prevent CD28-mediated Foxp3 transcription in CD4 + CD25- T lymphocytes.Exp Hematol. 2007; 35: 416-425Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 34Maroof A. Beattie L. Zubairi S. Svensson M. Stager S. Kaye P.M. Posttranscriptional regulation of ll10 gene expression allows natural killer cells to express immunoregulatory function.Immunity. 2008; 29: 295-305Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 35Deniz G. Erten G. Kücüksezer U.C. Kocacik D. Karagiannidis C. Aktas E. et al.Regulatory NK cells suppress antigen-specific T cell responses.J Immunol. 2008; 180: 850-857Crossref PubMed Google Scholar, 36Kheradmand T. Trivedi P.P. Wolf N.A. Roberts P.C. Swanborg R.H. Characterization of a subset of bone marrow-derived natural killer cells that regulates T cell activation in rats.J Leukoc Biol. 2008; 83: 1128-1135Crossref PubMed Scopus (6) Google Scholar, 37Lo C.K. Lam Q.L. Sun L. Wang S. Ko K.H. Xu H. et al.Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin-17 production.Arthritis Rheum. 2008; 58: 2700-2711Crossref PubMed Scopus (28) Google Scholar, 38Giuliani M. Giron-Michel J. Negrini S. Vacca P. Durali D. Caignard A. et al.Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15.PLoS ONE. 2008; 3: e2241Crossref PubMed Scopus (27) Google Scholar, 39Roy S. Barnes P.F. Garg A. Wu S. Cosman D. Vankayalapati R. NK cells lyse regulatory T cells that expand in response to an intracellular pathogen.J Immunol. 2008; 180: 1729-1736Crossref PubMed Google ScholarNK-22Skin, tonsils, gut mucosaIL-23IL-2240Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Abstract Full Text Full Text PDF PubMed Scopus (159) Google ScholarLN, Lymph nodes; NKreg, NK regulatory cell; PB, peripheral blood. Open table in a new tab LN, Lymph nodes; NKreg, NK regulatory cell; PB, peripheral blood. TGF-β– and IL-10–producing NK3-like cells have also been described.31Zhou R. Wei H. Tian Z. NK3-like NK cells are involved in protective effect of polyinosinic-polycytidylic acid on type 1 diabetes in nonobese diabetic mice.J Immunol. 2007; 178: 2141-2147Crossref PubMed Google Scholar 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.32Zhang C. Zhang J. Tian Z. The regulatory effect of natural killer cells: do “NK-reg cells” exist?.Cell Mol Immunol. 2006; 3: 241-254PubMed Google Scholar, 33Brillard E. Pallandre J.R. Chalmers D. Ryffel B. Radlovic A. Seilles E. et al.Natural killer cells prevent CD28-mediated Foxp3 transcription in CD4 + CD25- T lymphocytes.Exp Hematol. 2007; 35: 416-425Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar, 34Maroof A. Beattie L. Zubairi S. Svensson M. Stager S. Kaye P.M. Posttranscriptional regulation of ll10 gene expression allows natural killer cells to express immunoregulatory function.Immunity. 2008; 29: 295-305Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 35Deniz G. Erten G. Kücüksezer U.C. Kocacik D. Karagiannidis C. Aktas E. et al.Regulatory NK cells suppress antigen-specific T cell responses.J Immunol. 2008; 180: 850-857Crossref PubMed Google Scholar, 36Kheradmand T. Trivedi P.P. Wolf N.A. Roberts P.C. Swanborg R.H. Characterization of a subset of bone marrow-derived natural killer cells that regulates T cell activation in rats.J Leukoc Biol. 2008; 83: 1128-1135Crossref PubMed Scopus (6) Google Scholar, 37Lo C.K. Lam Q.L. Sun L. Wang S. Ko K.H. Xu H. et al.Natural killer cell degeneration exacerbates experimental arthritis in mice via enhanced interleukin-17 production.Arthritis Rheum. 2008; 58: 2700-2711Crossref PubMed Scopus (28) Google Scholar, 38Giuliani M. Giron-Michel J. Negrini S. Vacca P. Durali D. Caignard A. et al.Generation of a novel regulatory NK cell subset from peripheral blood CD34+ progenitors promoted by membrane-bound IL-15.PLoS ONE. 2008; 3: e2241Crossref PubMed Scopus (27) Google Scholar, 39Roy S. Barnes P.F. Garg A. Wu S. Cosman D. Vankayalapati R. NK cells lyse regulatory T cells that expand in response to an intracellular pathogen.J Immunol. 2008; 180: 1729-1736Crossref PubMed Google Scholar Most recently, mucosa-associated IL-22–producing NK cells have been discovered and are called NK-22 cells.40Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar 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.40Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 41Zenewicz L.A. Flavell R.A. IL-22 and inflammation: leukin' through a glass onion.Eur J Immunol. 2008; 38: 3265-3268Crossref PubMed Scopus (59) Google Scholar Interestingly, NK-22 cells do not produce IL-17,40Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar although conventional NK cells are able to release this cytokine.42Roark C.L. Simonian P.L. Fontenot A.P. Born W.K. O'Brien R.L. γδ T cells: an important source of IL-17.Curr Opin Immunol. 2008; 20: 353-357Crossref PubMed Scopus (173) Google Scholar, 43Benghiat F.S. Charbonnier L.M. Vokaer B. De Wilde V. Le Moine A. Interleukin 17-producing T helper cells in alloimmunity.Transplant Rev. 2009; 23: 11-18Abstract Full Text Full Text PDF Scopus (23) Google Scholar (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 known44Louten J. Boniface K. de Waal Malefyt R. Development and function of TH17 cells in health and disease.J Allergy Clin Immunol. 2009; 123: 1004-1011Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). 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.45Hanna J. Gonen-Gross T. Fitchett J. Rowe T. Daniels M. Arnon T.I. et al.Novel APC-like properties of human NK cells directly regulate T cell activation.J Clin Invest. 2004; 114: 1612-1623Crossref PubMed Google Scholar 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 al46O'Leary J.G. Goodarzi M. Drayton D.L. von Andrian U.H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells.Nat Immunol. 2006; 7: 507-516Crossref PubMed Scopus (289) Google Scholar 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.46O'Leary J.G. Goodarzi M. Drayton D.L. von Andrian U.H. T cell- and B cell-independent adaptive immunity mediated by natural killer cells.Nat Immunol. 2006; 7: 507-516Crossref PubMed Scopus (289) Google Scholar 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.47Sun J.C. Beilke J.N. Lanier L.L. Adaptive immune features of natural killer cells.Nature. 2009; 457: 557-561Crossref PubMed Scopus (366) Google Scholar Memory-like NK cells in the mouse have likewise been described by Cooper et al.48Cooper M.A. E