natural killer cells: versatile roles in autoimmune and infectious diseases

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Natural killer (NK) cells mediate the early, nonadaptive responses against virus-, intra-cellular bacteria- and parasite-infected cells, and modulate the activity of other effector cells of the innate and adaptive immune systems [1]. NK cells mediate these effects through the produc-tion of cytokines and via direct killing of trans-formed or infected cells. One major property of these large granular cytotoxic lymphocytes is the ability to kill tumor or virus-infected cells spontaneously, without the necessity for prim-ing that cytotoxic T cells require, and this abil-ity is not restricted by MHC expression of the target cell [2]. Although NK cells are commonly viewed as cytotoxic innate lymphocytes, there is increasing evidence that NK cells include distinct subsets with disparate repertoires, loca-tions, functions and developmental origins [3]. The diversity of human and mouse NK-cell subsets suggests that at least some of these sub-sets may be generated through different devel-opmental pathways. NK cells are derived from CD34+ hematopoietic stem or progenitor cells and undergo maturation primarily in the bone marrow [4,5]. IL-15 appears to be the crucial fac-tor for the development of human and murine NK cells [6,7]. Moreover, some NK-cell precur-sors may migrate into peripheral tissues, where

the local microenvironment influences their development. These varied developmental path-ways may endow NK cells with extraordinary functional plasticity, providing distinct effector functions in different tissues [8].

NK cells constitutively express several recep-tors for monocyte-derived cytokines, including IL-1, IL-10, IL-12, IL-15 and IL-18, and prob-ably receive their earliest activation signals from monocytes during innate immune responses [9–12]. Higher expression of some of these recep-tors, including IL-1RI and IL-18R (IL-1 recep-tor-related protein [IL-1Rrp]) has been noted in the CD56bright subset [9,10]. NK cells can be acti-vated by various cytokines, such as IFN -g, IL-2, IL-12, IL-15 and IL-18, leading to an increase in their number and cytotoxic activity, and thereby killing of a broader spectrum of targets, includ-ing some that are not generally affected by NK cells. This is probably related to the change in the cytokine environment that can induce specific molecules on both NK cells as well as target cells to support cell adhesion and to mediate cytolysis of NK-cell-resistant targets [13]. It is well known that NK cells use multiple mechanisms to lyse different target cells. Among them, the perforin/granzyme B-based pathway appears to be the pre-dominant cytolytic pathway [14]. In addition to

Esin Aktas, Gaye Erten, Umut Can Kucuksezer and Gunnur Deniz†

†Author for correspondenceDepartment of Immunology, Institute of Experimental Medicine (DETAE), Istanbul University, Vakif Gureba Caddesi, Sehremini 34393, Istanbul, Turkey Tel.: +90 212 414 2097 Fax: +90 212 532 4171 [email protected]

Natural killer (NK) cells are essential members of innate immunity and they rapidly respond to a variety of insults via cytokine secretion and cytolytic activity. Effector functions of NK cells form an important first line of innate immunity against viral, bacterial and parasitic infections, as well as an important bridge for the activation of adaptive immune responses. The control of NK-cell activation and killing is now understood to be a highly complex system of diverse inhibitory and activatory receptor–ligand interactions, sensing changes in MHC expression. NK cells have a functional role in innate immunity as the primary source of NK-cell-derived immunoregulatory cytokines, which have been identified in target organs of patients suffering from autoimmune diseases, and play a critical role in early defense against infectious agents. This review focuses on recent research of NK cells, summarizing their potential immunoregulatory role in modulating autoimmunity and infectious diseases.

Keywords: autoimmunity • cytokines • cytotoxic activity • infectious diseases • NK cells

Natural killer cells: versatile roles in autoimmune and infectious diseasesExpert Rev. Clin. Immunol. 5(4), 405–420 (2009)

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Review Aktas, Erten, Kucuksezer & Deniz

natural cytotoxicity, NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) through the low-affinity Fc recep-tor for IgG (FcgRIII; CD16). Several endogenous cytokines, such as IL-15, in conjunction with IFN-g, IL-12 and IL-18, have been shown to stimulate NK-cell cytotoxicity in the primary host defense against pathogens [15,16]. NK cells can also act independ-ently of perforin by NK-cell-dependent death receptor-mediated apoptosis. These molecules and receptors are part of the TNF family of ligands and their receptors. Two of these ligands, the Fas ligand (FasL; APO-1, CD95) and the TNF-related apoptosis-inducing ligand (TRAIL, APO-2L) are expressed on NK cells and both ligands have corresponding receptors on the target cells [17,18]. Receptor–ligand interactions by which target cells trigger natural cytotoxicity are still poorly defined, although it is becom-ing increasingly clear that the final outcome of NK-cell activity results from a balance between triggering and inhibitory receptors and ligands [19].

Distinct NK-cell subsetsHuman NK cells can be divided into two subsets, by their distinct phenotypic and functional properties, based on their cell-surface expression density of CD56 (CD56bright and CD56dim) [20]. NK cells express CD56 and CD16 at different levels; 90% of NK-cell populations express CD16 at high levels (CD16bright) and CD56 at low levels (CD56dim); whereas the remaining 10% express CD16 at low levels (CD16low) and CD56 at high levels (CD56bright) [21] (Figure 1). Early studies of resting CD56dim NK-cell popula-tions revealed that these cells are naturally more cytotoxic when

compared with CD56bright subsets; nevertheless, after activation with IL-2 or IL-12 in vitro, or following low-dose therapy with IL-2, the CD56bright and CD56dim subsets both exhibit similar levels of cytotoxicity [22,23]. Consistent with differences in their resting cytotoxic potential, CD56dim NK cells are more granular than CD56bright cells, although one report demonstrates similar levels of perforin expression in freshly isolated CD56bright and CD56dim NK cells shown by immunohistochemistry [22,24].

NK cells differ in their chemokine receptor expressions, and NK-cell subsets express CCR1, CCR4, CCR5, CCR6, CCR7, CCR9, CXCR5 and CXCR6, suggesting that peripheral blood NK cells, primarily the CD56bright cells, may vary in their abilities to migrate to different tissues. CCR1 and CCR5 are chemok-ine receptors that have been implicated in response to inflam-mation, suggesting that subsets of CD56bright and CD56dim NK cells have the capacity to migrate to sites of inflammation. CCR7 is critical for the entry of leukocytes into secondary lymphoid

organs such as lymph nodes. Results support the hypothesis that CCR7+ CD56bright NK cells are immunoregulatory cells with roles inside secondary lymphoid organs, whereas CCR7- CD56dim NK cells are cytotoxic effectors maintained in the peripheral blood [25]. Human NK cells cultured in the presence of IL-12 or IL-4 dif-ferentiate into cell populations with distinct patterns of cytokine secretion similar to Th1 and Th2 cells. NK cells cultured in the presence of IL-12 (NK1 cells) produce IL-10 and IFN-g, whereas NK cells cultured with IL-4 (NK2 cells) produce IL-5 and IL-13. Although these NK-cell subsets do not differ in their cytotoxic

activity, NK1 cells express higher levels of cell surface CD95

Figure 1. Human natural killer cells can be divided into two functional subsets based on their surface expression of CD56, CD56bright immunoregulatory cells and CD56dim cytotoxic cells, and result in different functions. The CD56bright NK cells produce high, whereas CD56dim NK cells produce low levels of cytokines in response to monokine stimulation. ADCC: Antibody-dependent cellular cytotoxicity; KIR: Killer cell Ig-like receptor; LAK: Lymphokine-activated killer; NK: Natural killer. Redrawn with permission from [180].

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ReviewNatural killer cells: versatile roles in autoimmune & infectious diseases

Early on during an infection, before antigen-specific T cells are expanded, NK cells may become activated and amplify the matu-ration of DCs induced by microbial products or virus-induced IFN, simplifying the activation and expansion of antigen-specific naive T cells. The activated NK cells could also provide imma-ture DCs with antigenic cellular material to be internalized and presented to T cells upon maturation [40]. It was also reported that NK and NKT cells might be functionally linked in vivo, and NKT cells, via their glycolipid ligand, rapidly induce a cascade of cellular activation that involves elements of innate and adaptive immunity [41].

In vitro experiments have shown that activated human NK cells can kill DCs, probably contributing to inhibition of T-cell activation in inflamed tissues [42]. It has been reported that in MHC class I-positive bone marrow host grafted with MHC class I-negative bone marrow, development of MHC class I-deficient thymocytes is delayed as a result of NK-cell cytotoxicity. Recently, it has been demonstrated that immature DC clearance is partly mediated by NK cells [43,44]. It appears that lymph node NK cells may have an important role in the initiation of T-cell responses by contributing to DC maturation [42]. The reciprocal crosstalk between NK cells and DCs that is induced by microbial prod-ucts promotes both rapid innate responses against pathogens and favors the generation of appropriate downstream adaptive responses [45]. Thus, these two cell types can work in concert to generate a maximal adaptive response.

NK-cell repertoireIn order for NK cells to defend the body against viruses and other pathogens, they require mechanisms that enable the determina-tion of whether a cell is infected or not. Unlike T and B lym-phocytes, NK cells express a variety of surface receptors that have either activating or inhibitory functions. Most of these receptors are not unique to NK cells and can be present in other T-cell subsets as well [46]. NK cells also discriminate between self and nonself by monitoring the expression of MHC class I molecules. According to the ‘missing-self ’ hypothesis, cells that express self-MHC class I molecules are protected from NK cells, but those that lack this self marker are eliminated by NK cells. Recent work has shown that there is another system of NK-cell inhibition, which is independent of MHC class I molecules [47,48].

In human NK cells, natural killer receptor (NKRs) can be cate-gorized as receptors including the killer cell Ig-like receptor (KIR) family, the leukocyte immunoglobulin-like receptor (LILR) fam-ily, NKR-P1, and the family of CD94/NKG2 lectin-like recep-tors [46,49]. There are 16 different KIR genes that are encoded on chromosome 19q13.4 [50]. Some members of the KIR family bind specifically to certain HLA class I allotypes. The KIR family is subdivided into two subfamilies based on their structure. KIRs are named according to whether they have two domains (2D) or three domains (3D; D0, D1, D2), and according to whether they possess a short (S) or long (L) cytoplasmic tail. KIRs with a long cytoplasmic tail contain immunoreceptor tyrosine-based inhibi-tory motifs and have an inhibitory function, whereas KIRs with a short cytoplasmic tail can activate NK- or T-cell responses [51,52].

(Fas) antigen than NK2 cells and are more sensitive to antibody or chemically induced apoptosis [26]. In vivo existence of human NK1- and NK2-cell subsets was demonstrated in freshly purified IFN-g-secreting and non-IFN-g-secreting NK-cell subsets from the peripheral blood of healthy individuals [27]. Several recent reports have identified NK cells with regulatory functions [28,29]. Bee venom major allergen, phospholipase A2 (PLA2) and purified protein derivative of Mycobacterium bovis (PPD)-stimulated T-cell proliferation experiments showed the effect of IL-10-secreting NK cells on antigen-specific T-cell responses. In this study, IL-10-secreting NK cells significantly suppressed both allergen- and antigen-induced T-cell proliferation as well as secretion of IL-13 and IFN-g, particularly due to secreted IL-10 as demonstrated by blocking of the IL-10 receptor (Figure 2). These data support that a small fraction of NK cells display regulatory functions similar to T-regulatory cells in humans [29]. Recently, the new NK-22-secreted NK cells, which secrete IL-22, IL-26 and leukemia inhibitory factor, were characterized. NK-22 cells were found in both human and murine mucosa-associated lymphoid tissues [30].

Immunoregulatory functions of NK cells It has been previously shown that NK cells are rarely found in lymph nodes and the lymphatic system, and that NK-cell assigned functions, such as the clearance of virally infected cells, primarily occur in the circulation. According to previous studies in rats, large granular lymphocytes do not normally recirculate between the blood and the lymph [31], and findings indicate that NK cells have increased turnover rates during viral infection, and that this increase in turnover is accompanied by NK-cell division [31,32]. A study performed with H-2-deficient nonmetastatic B16 melanoma cells demonstrated a negative correlation between surface expres-sion of tumor MHC molecules and NK-cell activity in circulation.Interferon treatment increases their level of MHC gene expression and simultaneously restores the cytotoxicity of NK cells [33].

The CD56bright CD16– cell subset is also found at low frequen-cies in secondary lymphoid organs, such as the lymph nodes and tonsils, and these cells respond vigorously to locally produced IL-2 [34]. In the peripheral blood, the predominant NK-cell popula-tion (>90%; CD56dim CD16+) is perforin rich and specialized for cytotoxicity, while the minor peripheral population (<10%; CD56bright CD16–) is also found in the T-cell areas of the lymph nodes [34,35]. Differential expression of L-selectin and lymphocyte function-associated antigen-1 on CD56bright and CD56dim NK subsets and chemokine receptors strongly suggest unique migra-tory properties and functions of these cells during the early immune response to foreign pathogens [36,37]. CD56bright NK cells are the major cytokine-producing subset of human NK cells that are found in T-cell areas.

Dendritic cells (DCs) are known to induce the growth and function of NK cells and they might play an important role dur-ing DC-mediated T-cell priming and polarization in T-cell areas of secondary lymphoid organs [38,39]. The studies regarding the interaction between human peripheral blood NK cells and mono-cyte-derived DCs upon the activation and/or maturation of either cell type show a potent crosstalk between NK cells and DCs.



Inhibitory receptors on the NK-cell surface initiate an inhibitory signal whereas acti-vating receptors trigger NK-cell activation and target cell lysis. Inhibitory receptors on the NK-cell surface recognize and engage their ligands (MHC class I molecules on the surface of the target cell) and a nega-tive signal is generated, thereby initiating an inhibitory signal. Activating receptors bind ligands on the target cell surface and trigger NK-cell activation, resulting in tar-get cell lysis [5]. Inhibitory KIRs may play an important role in immune regulation by actively inducing peripheral tolerance,

through enhancing the survival of effector cells and by dampening immune cascades; whereas stimulatory KIRs have been impli-cated in active host defense against infec-tious organisms [53,54]. The second family of receptors is composed of two subunits: CD94 paired with one member of the

NKG2 family of proteins. There are at least five members of the NKG2 family, includ-ing NKG2A, NKG2C, NKG2D, NKG2E and NKG2F [21,22]. The CD94–NKG2A heterodimer transmits signals that lead to the inhibition of the lytic process, other NKG2 receptors are NK-activating recep-tors [55,56]. Numerous studies suggest that this heterodimer recognizes a broad panel

of classical HLA class I molecules [57].This killing is mediated via the natural

cytotoxicity receptors, including NKp46, NKp44 and NKp30, known to be acti-vating receptors important in recognizing tumor cells in a MHC-independent man-ner. It was shown that NKp46 and NKp30 are constitutively expressed by all periph-eral blood NK cells and are not found on other immune cells [58]. NKp44 is not expressed by resting NK cells but is upreg-ulated on NK cells after IL-2 stimulation

and may be important for the cytotoxicity of IL-2-activated NK cells [5,49,58,59]. The viral hemagglutinin protein was recently identified as the ligand for the NKp46 receptor [60].

NK cells in autoimmune diseasesInappropriate activation of T or B lympho-cytes usually leads to autoimmune diseases resulting in systemic or organ-specific damage. Autoimmune diseases occur after a priming period, which is followed by homing of the target organ and tissue

Figure 2. Suppressive effect of IL-10-secreting natural killer cells on antigen-specific CD4+ T-cell proliferation. (A) IL-10 and IL-13 are determined in phospholipase A-stimulated PBMC of bee venom-sensitized individuals, and IFN-g is detected in PPD-stimulated PBMC. IL-10-secreting NK cells significantly suppressed IL-13 and IFN-g production, whereas IFN-g-secreting NK cells did not exert any suppressive effect. (B & C) To further investigate which cell subset is proliferating and inhibited by IL-10-secreting NK cells, PBMC were labeled with CFSE and stimulated with PPD and anti-CD3 monoclonal antibodies. IL-10-secreting NK cells significantly suppressed the proliferation of CD4+ T cells stimulated by PPD, but not by anti-CD3. These data demonstrate that the suppressor activity of IL-10-secreting NK cells on antigen-specific T-cell proliferation may play a regulatory role similar to T-regulatory cells in humans [29].*p < 0.01.CFSE: Carboxyfluorescein succinimidyl ester; NK: Natural killer; PBMC: Peripheral blood mononuclear cell; PPD: Purified protein derivative; US: Unstimulated.Redrawn with permission from [181]. © 2008. The American Association of Immunologists, Inc.

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destruction [61,62]. NK cells play important roles in all phases leading to autoimmunity. Recent studies indicate their activa-tion in animal models and in humans, especially in the stimula-tion and suppression of autoimmunity [63–65]. Some associations are found between activatory KIR or KIR/HLA genotypes and autoimmunity. Scleroderma is a good example for this associa-tion, in which activatory KIR2DS2 plays an important role in the disease [66]. It might be expected that if the existence of KIR/HLA genotypes that tune NK cells in favor of activatory interactions are advantageous in some infectious disease settings, these might tend to predispose to autoimmunity in some cases. Another pos-sible axis for the modulation of NK cells in autoimmunity comes from the fact that the activating receptor NKG2D can recognize endogenous stress-induced ligands. Roles attributed to NK cells in various clinical and experimental autoimmune diseases include, on one hand, a pathogenic function through inappropriate activa-tion and, on the other hand, suppressive functions through lysis of DCs or activated T cells [51,67].

Depending on the disease model used, NK cells may have pro-tective or disease-promoting effects. In multiple sclerosis (MS), NK cells were shown to have high expression of CD95 (Fas) on their surface. Autoimmune T cells mediating inflammatory responses in the CNS may be suppressed by NK cells with high CD95 expres-sion [68]. NK cells secrete Th2 cytokines such as IL-5 in the remis-sion period of MS; on the other hand, during the relapse of MS, they lose their NK2-like cytokine production. As with Th2 cells, NK2 cells are shown to inhibit Th1 cells in vitro; this finding may suggest the NK2 cells might also block the auto immune effector cells in vivo. As a result, NK cells may be especially important in the remission of MS [68,69]. A good murine model for MS is that of experimental autoimmune encephalomyelitis (EAE), which can be induced by sensitization against the CNS myelin. NK cells have a protective effect in mouse myelin oligodendrocyte glyco-protein (MOG)-induced EAE, and in vivo depletion of NK cells leads to worsening of the disease by increased proliferation of Th1 cytokines by CD4+ T lymphocytes in vitro, although a study has suggested that IFN-g does not have any role in the protective effect of NK cells [70]. The same effect of NK cells was also shown in rats with EAE; in the case of NK-cell depletion, the disease becomes aggravated [71]. A study performed in IL-18-deficient mice with EAE showed a defect in the Th1 response, leading to a resist-ance to MOG35–55 peptide-induced EAE. In this study it was also shown that IL-18 can direct autoreactive T cells and promote autodestruction in the CNS by the induction of IFN-g produced by NK cells [72]. EAE is aggravated by IL-21 but the effect of this cytokine can be abrogated by the depletion of NK cells. This find-ing may suggest thst IL-21 has different actions in the autoimmune response against neuroantigens [73]. Studies have demonstrated lysis of autologous neurons by activated NK cells in vitro, leading to the suggestion that NK-cell cytotoxicity may have an important role in EAE [74,75].

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with the presence of autoantibodies against nuclear antigens. Patients with SLE are susceptible to infectious organ-isms owing to a decreased number of NK cells [76]. Serum levels

of IFN-a were shown to increase in active SLE, but the same increase was not detected in inactive SLE patients. NK cells showed low numbers of Fc receptors in SLE [77], and CD56bright NK cells were shown to be elevated in blood samples of SLE patients [78]. The only identified gene with polymorphisms associ-ated with SLE appearing relevant to NK cells is the one encoding the CD16 receptor, the alteration in the expression of which also alters NK cell adhesion and function, which is detected to play a role in SLE pathogenesis [79]. Mice demonstrating the lymphopro-liferation (lpr) mutation develop lymphadenopathy and express a SLE-like autoimmunity resulting from defects in the Fas antigen gene [80]. This suggests that the killing defect in NK cells may be the immunological mechanism underlying childhood SLE [81].

Myasthenia gravis (MG) is a prototypic antibody-mediated neurological autoimmune disorder, characterized by autoanti-bodies against the acetylcholine receptor (AchR). Murine models of other autoimmune diseases suggest that NK cells may also participate in the initiation of autoimmunity through interactions with autoreactive T and B cells. Repeated immunizations with Torpedo AchR with adjuvant induced experimental autoimmune MG (EAMG) in susceptible mice. The disease severity may be decreased by depletion of NK cells before immunization, leading to low anti-AchR production, but NK-cell depletion after the initial immunization does not affect the development of EAMG [82]. Decreased NK-cell function has been observed in fulmi-nant MG [83]. AchR-immunized IL-21R-deficient mice develop exacerbated autoimmunity. Thus, NK-cell degeneration may act as a means evolved by the immune system to control excessive autoimmunity [84].

Psoriatic arthritis (PsA) is an inflammatory arthritis charac-terized by the presence of associated psoriasis and is classified among the rheumatoid factor-negative, HLA-B*27-associated

spondyloarthropathies [85]. Studies performed in PsA patients analyzing KIR expression show that there is a strong effect of carrying KIR2DS1 and/or KIR2DS2 on the risk of PsA and this effect is being enhanced in the absence of ligands for the inhibitory receptors, KIR2DL1 and KIR2DL2/3, respectively. A study suggested a model of susceptibility to PsA conferred by HLA-Cw ligand homozygosity such as to minimize inhibitory signals counterbalancing KIR2DS1 and/or KIR2DS2 [86].

HLA-B27 presence was also found to be strongly associated with spondylarthritides (SpA), making it of interest to determine whether this may involve the interaction with KIR3DL2 [87]. NK cells were also investigated in rheumatoid arthritis (RA), and sev-eral studies have investigated the potential involvement of NK cells. All studies detected NK-cell-like lymphocytes in the joints but results concerning their cytotoxicity were conflicting [88]. Studies performed in synovial fluid samples of RA patients detected the production of IL-10 and TGF-b by NK cells, suggesting their sig-nificant potential role in the formation of the cytokine milieu in arthritic joints [89]. In vitro experiments have shown that IL-15 pro-vides an appropriate stimulus to the expression of CD94/NKG2-A, but not to other class I-specific NK receptors, in the process of maturation of NK cells from thymocyte precursors [90]. High IL-15 levels were detected in the joints of patients with RA [91].



In patients with systemic-onset juvenile rheumatoid arthritis (JRA), the number of NK cells was found to be decreased [92] and a similar decrease was detected in NK-cell function studies per-formed in systemic-onset JRA patients with macrophage activation syndrome or hemophagocytic lymphohistiocytosis [93,94].

Behçet’s disease (BD) is a multisytemic vasculitis character-ized by oral and genital ulceration, other skin lesions, uveitis and manifestations affecting the blood vessels, CNS and gastro-intestinal system. The number of NK cells with diminished activity was increased in peripheral blood samples of patients with active BD [95,96]. The increase in the natural cytotoxic activity of NK cells in the inactive period of the disease may play a role, together with other immune mechanisms, in the etiopathogenesis of BD [97]. KIR3DL1 (p70) found on NK cells binds residues 77–83 of HLA-B alleles which have been desig-nated as Bw4 by serology and are shared by the BD-associated HLA-B alleles B*5101 and B*2702 [98]. CD56+CD16+ NK cells and CD3+ T cells showed an enhanced CD94 expression in BD patients, suggesting a possible regulatory role of NK recep-tors. The increase in CD94 expression of NK cells indicates their pathogenic and/or regulatory role in BD. The absence of a correlation between KIR3DL1 expression and the HLA-Bw4 motif was also shown [99]. Recent studies also point to a direct pathogenic role for HLA-B51 in BD [100]. We investigated the contribution of NK cells to the pathogenesis of BD in patients with uveitis. Intracytoplasmic TNF-a, IFN-g, IL-2, IL-4, IL-5, IL-10, IL-12 and IL-13 levels of purified NK cells from BD patients during relapse and remission periods were inves-tigated by flow cytometry. The TNF-a content was statistically increased in the relapse period compared with the remission period and healthy subjects. By contrast, high levels of IL-2 in relapse periods, and IL-10 in remission periods, were observed. These results may demonstrate the contribution of NK cells to the pathogenesis of BD owing to their NK1 profile in the relapse period and their NK2 profile in the remission period. NK cells may have regulatory effects owing to their IL-10 secretion in the remission phase [Kucuksezer UC, Aktas E, Gul A, Tugal-Tutkun I,

Deniz G, Unpublished data]. Insulin-dependent diabetes mellitus is a chronic autoimmune

disease characterized by specific destruction of pancreatic b cells, resulting in an absolute lack of insulin [101]. NK cells have been suggested to play a pathogenic role during the late stages of auto-immunity in a virally induced model of autoimmune diabetes [102]. Enterovirus infection is a good model for direct evidence of b-cell infection associated with inflammation and functional impairment in Type 1 diabetic patients [103]. Depletion of NK cells actually inhibited the development of diabetes in two different mice models, suggesting a role for NK cells in diabetes [104]. It has been established that intrapancreatic NK cells were increased in the accelerated onset of diabetes in two mice models, namely NOD and NOR RIP–IFN-b transgenic mice. In the same study, the authors were able to show the hyperexpression of cytokines involved in NK-cell function and migration in the pancreas of diabetic mice. The depletion of the NK cells in vivo completely stopped the acceleration of diabetes [105].

Human NK-cell activity was found to be decreased in new-onset Type 1 diabetes, but the activity was similar in Type 2 diabetics compared with control subjects. During the remission period of Type 1 diabetes, NK-cell cytotoxic activity increased in most subjects, suggesting a dichotomy in NK and islet killer cell activities in new-onset Type 1 diabetes, which could have an important role in the pathogenesis of Type 1 diabetes [106]. The same decrease in NK-cell cytotoxicity was also observed in rats [107,108]. Studies investigating the influence of KIR and HLA 1 genes on the susceptibility to develop Type 1 diabetes showed that patients expressed increased numbers of activating KIR genes compared with healthy individuals, and activating KIR molecules may induce T-cell-mediated immune responses in the presence of their specific HLA ligand [109,110].

NK cells in infectious diseaseNK cells are an important component of the innate immune response against many viruses and pathogens. Recognition of infection by NK cells is accomplished by the activation of receptors on the NK-cell surface, which initiates NK-cell effec-tor functions. They have ability to lyse virus-infected cells, to secrete cytokines that inhibit viral replication and to activate and recruit cells of the adaptive immune response. Recent studies have focused on the mechanisms by which NK cells recognize and respond to viruses, parasites and bacteria, and on the unique role of NK cells in innate immunity to infection [111]. Human NK receptors and coreceptors that are involved in different infectious diseases are summarized in Table 1.

NK cells in HIV infectionNK cells might have an important role in host defense against HIV infection, as well as in the control of HIV replication in vivo. HIV is able to escape cytotoxic T-lymphocyte recogni-tion by downmodulation of MHC class I receptors, which should enhance NK-cell cytotoxicity against infected targets. However, HIV has evolved elaborate mechanisms to evade NK-cell responses. Moreover, NK-cell function is compromised through poorly understood mechanisms as a result of viremia [112,113].

Activated NK cells function via cytokine secretion or direct cyto-lysis of target cells; DCs are thought to make critical contributions in the activation of both of these functions. Although the magni-tude and physiological relevance of DC-mediated NK-cell activa-tion in vivo is not completely understood, there is the question of mechanisms controlling AIDS-associated infections, particularly respiratory infections [51,114–116]. It has also been reported that the CD56dim CD16+ NK subset is decreased in HIV-infected individu-als, indicating a selective defect in mature CD56dim NK cells and probably an impaired production of immunoregulatory cytokines, such as IL-2 or IL-21 by CD4+ T lymphocytes, whereas no sig-nificant changes are observed in the CD56bright population [117]. Moreover, in uninfected individuals, the CD56- CD16+ subset of NK cells, which is present in an extremely low percentage of individ-uals, is common in HIV-1-seropositive subjects [118]. HIV-exposed but uninfected subjects have been reported to have enhanced NK functions and increased IFN-g and TNF-a levels [119]. By contrast,



during chronic HIV infection, NK-cell cytotoxic function has long been known to be reduced in subjects with AIDS [120]. Loss of NK-cell activity and frequency has been correlated with HIV disease progression, particularly in individuals with opportunistic infec-tions. The relevant reduction of NK-cell function is dependent on well-described perturbations in their expression of specific receptors, leading not only to the inhibition of their patrolling activity against invading pathogens, but also to alterations of their crosstalk with other cells of the immune system [116,121,122].

NK cells can impact on HIV infection through a number of dif-ferent effector mechanisms, for example, by the lysis of infected cells following class I downregulation or altered expression due to peptide loading, by antibody-dependent cell-mediated cytotoxicity, through effects of cytokine release on DC programming, and by the initiation of adaptive immunity through the release of chemokines [51]. The ability of an NK cell to kill relevant targets such as virally infected cells depends on a delicate balance of the patterns of expression of inactivating NKRs and activating receptors [123]. HLA-B molecules can be categorized by the presence of a Bw4 or Bw6 molecular epitope. Remarkably, HLA-B molecules encoded by HLA-B alleles with the Bw4 epitope, but not the Bw6 epitope, serve as ligand for NK cell KIR [124]. It has been shown that suppression of HIV-1 viremia is significantly associated with homozygosity for HLA-B alleles that share the HLA-Bw4 epitope, and homozygosity for HLA-Bw4 alleles was also related to the ability to continue AIDS free and to retain a normal CD4+ T-cell count in a second cohort of HIV-1-infected individuals [125]. The protective role for HLA-B27 in HIV disease was explained by a specific and strong cytotoxic T-lymphocyte response against the p24 epitope, a conservative HIV protein [126].

It was demonstrated that expression of inactivating NKRs in HIV-infected viremic patients was well conserved and increased expression on NK cells as compared with healthy donors, and the major activating NK receptors, with the exception of NKG2D, were significantly downregulated [127].

The Bw4-80I group includes two alleles, B*57 and B*27, which are known to be highly protective in the acquired immune response against HIV based on both functional and genetic

epidemiological data [128]. By contrast, the influence of HLA-B*35

in accelerating progression to AIDS was completely attributable to HLA-B*35-Px alleles, some of which differ from HLA-B*35-PY

alleles by only one amino acid residue and carry the Bw6 motif (i.e. not the Bw4-80I motif), and these three alleles show the strongest effects on progression to AIDS [129]. The specific combination of the activating KIR allele KIR3DS1 with HLA-B alleles that encode molecules having isoleucine at position 80 (HLA-B Bw4-80I) was previously shown to be associated with delayed progression to AIDS in individuals infected with HIV-1 [115]. Based on this genetic asso-ciation, KIR3DS1 on NK cells was proposed to bind to HLA-B Bw4-80I on HIV-1-infected target cells, thereby signaling the NK cells to kill the targets. Findings indicated that this compound genotype also confers protection against the development of AIDS-defining opportunistic infections. Interestingly, no protection was observed against the development of AIDS-defining malignancies. The double protection of this compound genotype in AIDS, along with the specificity of its effects, is a novel finding and under-lines the role of host immunogenetics against HIV/AIDS [130]. It was shown that coexpression of KIR3DL1 and HLA-B57, which has been associated with a reduced risk of progressing to AIDS in HIV-infected individuals, also lowers the risk of HIV infection in exposed uninfected individuals [131].

It has been shown that NK cells from normal and HIV-1-positive donors produce CC chemokines and other unidenti-fied factors, such as MIP-1a, MIP-1b and RANTES, which can inhibit both macrophage- and T-cell-tropic HIV-1 repli-cation in vitro. The results indicate that NK cells may have an important role in the in vivo regulation of HIV-1 infection [132]. The studies interpreted that important CC chemokines may be secreted by activated NK cells in vivo and may suppress HIV replication by CC chemokine-mediated, in addition to NK-mediated, lytic mechanisms [133]. It was found that a lower frequency of CXCR4+ and a higher frequency of CCR5+ expres-sion on NK cells are positively correlated with the level of HIV viral loads and negatively correlated with CD4 T-cell counts, indicating that the expression of chemokine receptors on NK cells

Table 1. Human natural killer receptors and coreceptors involved in infectious diseases.

Infectious disease

NK receptors and coreceptors Function in disease Ref.

AIDS HLA-B27HLA-Bw4HLA-B*35-Px and HLA-B*35-PYKIR3DS1/HLA-B Bw4-80IKIR3DL1 and HLAB-57 coexpression

Protection from HIVSuppression of HIV-1 viremia Progression to AIDSDelayed progression to AIDSRisk of progression to AIDS

[126][125][129][115][131]

CMV KIR2DS2 and KIR2DS4Ly49HNKG2D

Decreasing risk of CMV reactivationTrigger NK-cell effector functions Initiate NK-cell function against infected cells

[151]

[142]

[148]

HCV KIR2DL3-HLAC1KIR3DS1-HLA-Bw4I80

Efficiently clearing HCVProtection from hepatocellular carcinoma

[161]

[162]

MTB NKp46 NKG2D

NK-cell-mediated lysis Lysis of MTB-infected monocytes

[173]

[174]

MTB: Mycobacterium tuberculosis; NK: Natural killer.



correlated with HIV disease progression [134]. Furthermore, there is an inverse correlation between the level of plasma viremia and the ability of NK cells and NK cell-derived supernatants to sup-press endogenous HIV replication in CD4+ T cells ex vivo [135]. It was shown that IL-15 restores NK cytotoxicity and deficient IL-12 production by peripheral blood mononuclear cells from HIV-infected individuals [136]. In vitro, IL-15 priming induced IFN-g and CC chemokine production in both viremic and aviremic patients, and the combination of IL-15 together with IL-12 was shown to be the most potent costimulus for CD69 expression and production of CC chemokines by NK cells [137]. In addition to IL-12 and IL-15, the effect of IL-21 and IL-15 on perforin expres-sion, proliferation, degranulation, IFN-g production and cytotox-icity were also investigated in vitro, and it has been reported that IL-15 upregulated perforin expression primarily in CD56 NK cells, implying that IL-21 and IL-15 together upregulated CD107a and IFN-g, as well as NK cytotoxicity [138]. Findings from an animal study supported the fact that IL-15 elicits IFN-g produc-tion in CD3– CD8+ NK cell subpopulations, and NK cells play a vital role in controlling HIV-1 infection in chimpanzees [139].

NK cells in CMV infectionSince the original description of an NK-cell-deficient patient who experienced repeated infections with herpes viruses, including human cytomegalovirus (HCMV), many studies have addressed the molecular mechanisms by which NK cells respond to CMV infection [140]. These NK-cell-depleted, virus-infected mice were found to be more susceptible to murine cytomegalovirus (MCMV) infection, as compared with control virus-infected mice. Additionally, depletion of NK cells renders resistant mice suscep-tible to MCMV infection, facilitating the use of in vivo systems to study this process [141]. Two recent studies have shown that Ly49H specifically recognizes the m157 glycoprotein encoded by MCMV and results in NK cell triggering m157, a member of the MCMV m145 gene family, which encodes a protein with puta-tive MHC class I-like structural homology [142]. Transfection of target cells with m157 renders them susceptible to lysis by trig-gering Ly49H+ NK cells, and interaction of Ly49H with m157 induces production of IFN-g and the chemokine ATAC/lympho-tactin [143,144]. The mechanisms involved in DC–NK cell interac-tions during viral infection showed that NK cells were efficiently activated by MCMV-infected CD11b+ DCs. DCs can directly enhance NK-cell cytotoxicity by activating the NKG2D receptor, or indirectly by producing IFN-g. Especially, adoptive transfer of MCMV-activated CD11b+ DCs resulted in improved control of MCMV infection, indicating that these cells participate in control-ling viral replication in vivo. [145]. It was shown that preferential NK-cell proliferation is dependent on DAP12-mediated signaling following the binding of Ly49H to its ligand, m157. Ly49H signaling through DAP12 appears to directly augment NK-cell sensitivity to low concentrations of proliferative cytokines such as IL-15 [146].

Human cytomegalovirus interferes with NK-cell functions at various levels. The HCMV glycoprotein UL16 binds some of the ligands recognized by the NK-activating receptor NKG2D, namely UL16-binding proteins (ULBP)-1 and -2 and MHC

class I-related chain B, possibly representing another mechanism of viral immune escape. Results showed that upon infection with HCMV, HCMV UL16 inhibits the induction of ‘infection-induced’ cellular ligands that bind the NKG2D-activating recep-tor, thereby suppressing this potential mechanism of NK cells [147]. NKG2D and Ly49H lectin-like molecules have shown to trigger NK-cell functions recognizing class I-related stress-inducible mol-ecules and the m157 MCMV glycoprotein [148]. UL141 in HCMV has also been shown to block surface expression of CD155, the ligand for the NK-cell-activating receptors CD226 and CD96 [149]. It has been reported that healthy HCMV-seropositive individuals displayed increased proportions of NK and T cells that expressed the triggering CD94/NKG2C killer lectin-like receptor, which binds HLA-E with a lower affinity than CD94/NKG2A [150]. After hematopoietic cell transplantation, it has been shown that activat-ing KIR genes are important for control of CMV reactivation. A donor-activating KIR profile, predictive of a low risk of CMV reactivation, contained either KIR2DS2 and KIR2DS4 genes [151].

NK cells in HCV infectionHepatitis C virus (HCV), a positive-stranded RNA virus, is the principal causative agent of parenterally transmitted, and is the major cause of, chronic liver diseases worldwide. HCV-infected individuals carry an increased risk of developing various liver dis-eases including cirrhosis and hepatocellular carcinoma. Infections with hepatotropic viruses activate liver NK cells, which play a criti-cal role in the recruitment of T cells to the liver. Activated NK cells can kill virus-infected cells via perforin/granzyme, and FasL path-ways, and produce proinflammatory cytokines, which can induce an antiviral state in host cells. Thus, NK cells could also poten-tially contribute toward HCV control. It would not be surprising that an adequate NK-cell response to hepatotropic viruses such as HCV may be controlled even in the absence of virus-specific immune responses. This observation is supported by the fact that, as in humans, a certain percentage of HCV-infected chimpanzees may recover from HCV infection by mechanisms other than the induction of readily detectable HCV-specific T-cell responses [152,153].

The potential importance of NK cells in the control of HCV infection was discounted in a study showing an essential role for memory CD8+ T cells in the long-term protection from chronic HCV infection in animal models [154]. The NK-cell-mediated noncytolytic effect on full cycle HCV infection of human hepatocytes was investigated and it was shown that human hepatocytes cocultured with NK cells or treated with supernatants from NK-cell cultures had significantly lower lev-els of HCV RNA and protein than control cells [155]. Several studies have reported that NK cells are functionally impaired in chronic HCV infection [156]. Cytokine-activated NK cells were shown to induce HCV-associated, perforin/granzyme- dependent lysis of human hepatoma cells and this was inde-pendent of MHC class I expression levels; however, on removal of cytokine stimulation, NK cells failed to exert any direct cytolytic effect on replicon targets [157]. An increased expres-sion of the MHC class I antigens (A, B or C) in HCV-infected cells may make them resistant to NK-cell-mediated lysis. Apart



from increasing the expression of MHC class I antigens, HCV also seems to enhance the expression of stress-inducible pro-teins (e.g., MICA). Increased expression of these proteins on hepatocytes have been reported [158].

The mechanisms by which HCV NK cells express CD94/NKG2A at considerably high levels remain elusive. One possibility is that the expression levels of NK receptors may be modified by various types of cytokines; for example, it was shown that TGF-b induces CD94/NKG2A expression [159]. As TGF-b can upregulate the expression of NKG2A on NK cells, high levels of serum TGF-b found in chronic HCV-infected patients suggest that TGF-b may contribute to the high expression of NKG2A on NK cells in chronic HCV infection [160]. It was shown that genes encoding the inhibiting NK-cell receptor KIR2DL3 and its HLA-C1 ligand directly influence the resolution of HCV infection [161]. It was found that the HLA-Bw4I80 epitope and the KIR3DS1 gene are more frequent in HCV carriers than in patients with hepatocellular carcinoma [162]. Ligation of an HCV receptor (CD81) inhibits NK cells, and the major HCV envelope protein E2 (HCV-E2) has been shown to bind to CD81. Cross-linking of CD81 by the major HCV-E2 or anti-CD81 antibodies blocks NK-cell activation, cytokine production, cytotoxic granule release and proliferation [163]. Similarly, another study showed that cross-linking CD81 on NK cells results in inhibition of cytokine production and non-MHC-restricted cytotoxic activity [164]. The defects observed in NK and memory T-cell lineages in IL-15-deficient mice confirm the essential role played by this cytokine in NK and T-cell generation and survival [7]. It was shown that in vitro stimulation with IL-15 rescued NK cells of HIV- and HCV-positive patients from apoptosis and enhanced proliferation and functional activity [165]. A study demonstrated that CD81 cross-linking via immobilized E2 or monoclonal anti-bodies specific for CD81 resulted in a significant reduction in IFN-g production by IL-12- or IL-15-activated NK cells, and these results suggest that one mechanism by which HCV may alter host defenses and innate immunity is via the early inhibition of IFN-g production by NK cells [164].

NK cells in Mycobacterium tuberculosis infection Both innate and adaptive immune systems contribute to host defense against infection with Mycobacterium tuberculosis. In most individuals infected with the causative agent M. tuberculosis, immunity is able to inhibit growth of the pathogen, leading to latent infection with persistent and dormant bacteria [166]. NK cells have been associated with early resistance to intracellular pathogens and are known to be potent producers of IFN-g. In C57BL/6 mice infected with M. tuberculosis, NK cells increased in the lungs over the first 21 days of infection, and these NK cells had increased expression of activation and maturation markers. These NK cells from infected lungs were capable of producing IFN-g and became positive for perforin. These findings indicate that NK cells can become activated during the early response to pulmonary TB in the mouse model and are a source of IFN-g, but their removal does not substantially alter the expression of host resistance [167]. Antimicrobial granulysin, present both in

NK and cytotoxic T cells, seems to be required for the control of human TB; this small, granule-associated peptide has been shown to kill M. tuberculosis and is delivered to intracellular mycobac-teria by perforin [168]. The observation that plasma granulysin levels and cellular IFN-g production correlate with curative host responses in pulmonary TB points to a potentially important role of granulysin, together with IFN-g, in host defense against M. tuberculosis [169].

NK-cell activity is controlled by cytokines (IL-12, IL-18 and IFN-a in particular) and a complex repertoire of activating (e.g., NKG2D, natural cytotoxicity receptors) and inhibitory receptors (e.g., CD94–NKG2A). Although in recent years it has become clear that NK cells are capable of mounting a vigorous response to M. tuberculosis, their exact function in vivo remains enigmatic. Purified NK cells from healthy or from HIV-1-infected subjects were shown to have elevated lytic activity against M. tuberculosis-infected monocytes after IL-2 or IL-12 stimulation. These data suggest an important involvement of NK cells and their activating stimuli (particularly IL-12) in host resistance to TB [170]. The effect of IL-15 on NK cells in patients with HIV and TB coinfection (HIV–TB) is unclear. The study examined the cytotoxic activ-ity and cytokine response of NK cells in HIV–TB after stimu-lation with IL-15 and IL-12/IL-2. Applying IL-15 and IL-12 in combination resulted in maximal NK-cell cytotoxicity [171]. The IL-15 transgenic mice showed strong resistance to infection with Mycobacterium bovis Bacille Calmette–Guérin (BCG), and over-expression of IL-15 in vivo enhanced protection against BCG infec-tion via augmentation of NK- and T-cell cytotoxic responses [172].

Human NK cells are known to directly lyse M. tuberculosis-infected monocytes and macrophages in vitro. The recognition is thought to be mediated by NKG2D and the natural cytotoxicity receptor NKp46 binding the stress-induced ligands ULPB1 and vimentin, respectively. NK-cell lytic activity against M. tuber-culosis-infected monocytes and NKp46 mRNA expression were found to be reduced in TB patients with ineffective immunity to M. tuberculosis compared with healthy donors. These investiga-tors suggested that the NKp46 receptor participates in NK-cell-mediated lysis of cells infected with an intracellular pathogen, and the reduced functional capacity of NK cells is associated with severe manifestations of infectious disease [173]. It was shown that expression of the activating receptors NKp30, NKp46 and NKG2D were enhanced on NK cells by exposure to M. tuber-culosis-infected monocytes, and anti-NKG2D and anti-NKp46 inhibited NK-cell lysis of M. tuberculosis-infected monocytes. Infection of monocytes upregulated expression of the NKG2D ligand, ULBP1. The dominant roles of NKp46, NKG2D and ULBP1 were confirmed for NK-cell lysis of M. tuberculosis-infected alveolar macrophages. Furthermore, TLR-2 contributes to upregulation of ULBP1 expression [174].

NK-cell functions are dependent on adequate levels of gluta-thione. It was shown that glutathione in combination with IL-2+ IL-12 augments NK-cell functions, leading to control of M. tuber-culosis infection [175]. Killing was not dependent upon exocytosis of NK-cell cytotoxic granules, and NK cells have been shown to express several surface ligands capable of initiating apoptosis [176].



Human NK cells may mediate killing of intracellular M. tuberculo-sis via an apoptosis-dependent but Fas/FasL-independent pathway [177]. Increased numbers and activity of regulatory T cells are also associated with depressed NK-cell activity in several diseases, and it was shown that M. tuberculosis-stimulated monocytes activated NK cells to lyse expanded regulatory T cells, and this was also inhibited by anti-NKG2D and anti-ULBP1, confirming the physi-ological relevance of this effect. A potential new role for NK cells in maintaining the delicate balance between the regulatory and effector arms of the immune response was also demonstrated [178]. Studies have shown that there is also intense crosstalk between DCs and NK cells in the presence of M. tuberculosis in vitro [40]. The depletion of monocytes increased the production of IFN-g by NK cells in TB patients. Therefore, monocytes from TB patients regulated the NK function involving IL-10, causing the downregu-lation of costimulatory/adhesion molecules and/or IFN-g produc-tion [179]. Further studies are needed to understand the role of NK cells in host defense against M. tuberculosis infection. Recent advances in understanding NKRs and their ligands might open up novel therapeutic techniques for infected individuals.

There is strong evidence that the innate immune system, in particular NK cells, influence subsequent adaptive immune responses. NK cells are able to kill abnormal cells rapidly to pro-duce cytokines activating other immune cells; therefore, these cells are being increasingly implicated in autoimmune and infec-tious diseases. Different HLA/KIR genotypes can impart differ-ent thresholds of activation to the NK-cell repertoire, and such genotypic variation has been found to confer altered risk in a number of diseases. Studies on the immunomodulatory roles and functions of NK cells in human and animal models may offer new insights into the mechanisms underlying protection from infectious and autoimmune diseases.

Expert commentaryThere is strong evidence that the innate immune system, in particu-lar NK cells, influence subsequent adaptive immune responses. NK cells were recognized over 30 years ago as being able to kill cancer cells in in vitro conditions. Since that time, a role for NK cells in activating other cells and in directing how the immune system responds to a wide range of infections has also been established. By virtue of their ability to rapidly kill abnormal cells and produce cytokines and chemokines, NK cells are positioned for a key role in regulating autoimmune responses, and defects in NK cells lead to autoimmune diseases or increased susceptibility to infectious diseases. Autoimmune diseases are inflammatory disorders, many of which have a suspected infectious etiology. NK cells may be involved in the initiation of autoimmunity and accumulate in the target organs of certain autoimmune diseases, and can either sup-press or augment autoimmunity, directly or indirectly. These cells also play a critical role in the early defense against infectious agents. The role of NK cells in antiviral innate immune responses has been well documented. It is clear that the right defense against viral pathogens is the harmony of NK cells and T cells. Studies demon-strated that human NK cells comprise distinct receptor-expressing and cytokine-producing subsets, similar to Th1 and Th2 cells.

The reciprocal relationship between Th1 and Th2 cells, exerted through the secretion of cytokines, could be an important future immunotherapeutic avenue to pursue. Future studies defining the molecules used by NK cells to interact with DCs, macrophages and T cells during immune responses against pathogens and tumors, as well as in autoimmunity, promise to reveal the importance of NK cells in the immune system. New compounds, mainly antibodies, will be designed to stimulate or inhibit NK-cell activity, and we need to consider more carefully how to use these therapies that affect NK cells, so as to maximize their beneficial role.

Five-year viewNatural killer cells play an important role in immune defense in cancer and infectious diseases, and in autoimmunity. NK-cell killing is regulated by positive or negative signals derived from the interaction of NK-cell surface receptors with ligands on target cells. Distinct types of immune response are controlled by the Th1 and Th2 subpopulations of T cells, discriminated on the basis of their cytokine secretion. Similar to Th1 and Th2 cells, the in vivo existence of human NK cell subsets was demonstrated in freshly isolated IFN-g-secreting and IFN-g-nonsecreting NK cells. The IFN-g-secreting NK-cell subset showed a typical cytokine pattern, with predominant expression of IFN-g but almost no IL-4, IL-5 and IL-13 expression. By contrast, IFN-g-nonsecreting NK cells mainly produce IL-13 and contribute to the production of IgE. Various studies have suggested that the timing, and possibly the localization, of IL-10 production critically affects the immune regulatory functions of NK cells. Recently, the in vivo existence of a regulatory NK-cell subset playing an immune regulatory and sup-pressor role was demonstrated. Studies provide new insights into the role of cytokines in the activation and homeostasis of NK cells and indicate distinct functions for human NK-cell subsets during the immune response. As a key effector of innate immunity, NK cells form a bridge between innate and adaptive immunity. To address the question of whether autoimmune diseases can be induced by infections, autoimmunity needs to be defined. Analyses of patient genotypes in a wide range of diseases has led to a model whereby genetic susceptibility to specific infectious diseases may be associ-ated with genotypes thought to favor a tendency to NK-cell inhibi-tion. Genotypes believed to frame the balance of NK-cell activation may be susceptible to some autoimmune diseases. An important issue for the future will therefore be to dissect the hetero geneity in NK-cell responses and their relationship to NK-cell subsets, the local cytokine environment and the expression pattern of activating and inhibitory cell surface receptors. Further research into the immuno-modulatory role of NK cells is likely to provide new insights into the pathogenesis of autoimmune and infectious diseases.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



Key issues

• Human natural killer (NK) cells can be subdivided into different populations based on the relative expression of the surface markers CD16 and CD56 (CD56bright CD16dim/- and CD56dim CD16+).

• NK cells have a functional role in innate immunity as the primary source of NK-cell-derived immunoregulatory cytokines.

• In addition to stimulatory cytokines, activating and inhibitory cell surface receptors that recognize self-MHC-I molecules also modulate NK-cell functions.

• NK cells play an important role in the pathogenesis of autoimmune and infectious diseases.

• Genetic factors and different anatomical sites of NK cells influence the pathogenesis of autoimmune diseases.

• NK cells lyse infected cells following MHC class I downregulation or antibody-dependent cellular cytotoxicity.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

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Affiliations• Esin Aktas, PhD

Department of Immunology, Institute of Experimental Medicine (DETAE), Istanbul University, 34393 Istanbul, Turkey Tel.: +90 212 414 2000 Fax: +90 212 532 4171 [email protected]

• Gaye Erten, MD, PhD Department of Immunology, Institute of Experimental Medicine (DETAE), Istanbul University, 34393 Istanbul, Turkey Tel.: +90 212 414 2000 Fax: +90 212 532 4171 [email protected]

• Umut Can Kucuksezer, MSc Department of Immunology, Institute of Experimental Medicine (DETAE), Istanbul University, 34393 Istanbul, Turkey Tel.: +90 212 414 2000 Fax: +90 212 532 4171 [email protected]

• Gunnur Deniz, PhD Department of Immunology, Institute of Experimental Medicine (DETAE), Istanbul University, Vakif Gureba Caddesi, Sehremini 34393, Istanbul, Turkey Tel.: +90 212 414 2097 Fax: +90 212 532 4171 [email protected]

natural killer cells: versatile roles in autoimmune and infectious diseases

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