The role of NK cells in autoimmune responses has been examined in several murine models of autoimmune diseases (reviewed in [25
]). The evidence from these studies (discussed below) suggests that NK cells can affect the development of autoimmunity through several mechanisms, including suppressing viral infections and potential subsequent autoimmune responses, modulating autoreactive responses of other immune cells, or, as effector cells, directly mediating tissue damage (Fig. ). Different NK cell responses in these models presumably result from alterations in the balance between inhibitory and stimulatory signals mediated through the interactions of NK cell receptors and their ligands. The expression levels of ligands for both inhibitory and activation NK cell receptors in target tissues as well as the immediate cytokine milieu modulate the NK cell activation threshold, allowing different NK cell responses that could potentially suppress or augment autoimmunity.
Figure 2 Murine models show that natural killer (NK) cells affect autoimmunity through several potential mechanisms. (a) NK cells limit viral-induced tissue damage by directly killing virally infected cells or by releasing cytokines that can suppress viral propagation (more ...)
Viral infections have been implicated in the pathogenesis of several autoimmune diseases due to molecular mimicry or polyclonal immune activation [64
]. It is well established that NK cells have a crucial role in the initial defense against viral infections [3
]. It is therefore not surprising that several investigators have attributed the impact of relative deficiencies of NK cell numbers or function seen in many autoimmune diseases to a decreased ability to respond to viral infections.
Results from mouse models show a role for NK cells in suppressing autoimmune responses after viral infections (Fig. ). For example, NK cells are important in preventing encephalitis in a murine model of MS induced by Theiler's murine encephalitis virus [65
]. Depletion of NK cells in resistant mice resulted in the development of diffuse encephalitis and meningitis early in the post-infection period [65
]. NK cells are also thought to prevent coxsackievirus B3 (CVB3)-induced myocarditis by limiting viral replication and thus preventing prolonged immune activation and minimizing tissue damage with exposure of self antigens. Infection with either CVB3 or murine cytomegalovirus resulted in chronic myocarditis in susceptible strains of mice, accompanied by the development of autoantibodies against cardiac myosin [66
]. Depletion of NK cells before infection with CVB3 rendered resistant strains of mice as sensitive to the development of myocarditis as susceptible strains of mice [66
]. Thus, NK cells may have a role in suppressing autoimmunity after viral infections by effectively limiting viral replication and subsequent tissue destruction.
Evidence from murine models also supports an immunoregulatory role for NK cells in modulating other immune cell responses (Fig. ). The development of autoimmunity in C57BL/6lpr
mice, which have a defect in Fas
, a gene encoding a tumor necrosis factor receptor superfamily member involved in inducing apoptosis, is temporally related to an age-dependent loss of NK and NKT cells. Furthermore, antibody-mediated NK cell depletion in these mice enhanced the development of autoantibody-secreting B cells, whereas the adoptive transfer of NK cells delayed the onset of autoantibody production [67
]. Studies in vitro
have shown that rat NK cells can inhibit autoreactive T cell cytokine production and proliferation [68
]. Indeed, depletion of NK cells worsened colitis in a CD4+
T cell transfer model in mice, demonstrating an immunoregulatory role for NK cells [69
]. Several investigators have reported similar findings in experimental autoimmune encephalomyelitis (EAE), a Th1-mediated mouse model of MS [70
]. Depletion of NK cells before immunization of sensitive mice with myelin oligodendrocyte glycoprotein (MOG35–55
) peptide resulted in clinically more severe, relapsing EAE [70
]. Depletion of NK cells also resulted in more severe disease after passive transfer of an EAE-inducing CD4+
T cell line, showing that NK cells are not only involved in the initiation of EAE but can inhibit effector T cells [70
]. NK cell depletion in rats before immunization with myelin basic protein also exacerbated the clinical features of EAE and increased mortality [71
]. However, these results conflict with a third study, which reported that NK cell depletion resulted in less severe clinical scores [72
]. Overall, NK cells appear to participate in regulating T and B cell-mediated autoimmune responses.
Less information is available on how NK cells perform this potential immunoregulatory role. It is possible that this role is mediated directly by the release of immunomodulatory cytokines and chemokines involved in lymphocyte recruitment, activation, and suppression, such as IFN-γ and transforming growth factor-β. However, NK cell-derived cytokines and chemokines may act indirectly by inducing cytokine production in other cells, activating macrophages, or supporting the maturation of dendritic cells (DCs). Indeed, bidirectional interactions between NK cells and other components of the innate immune system such as DCs and NKT cells have been reported ([73
]; reviewed in [9
]). It is also possible that the immunoregulatory role of NK cells is mediated by the killing of autoreactive lymphocytes or immature DCs by NK cells. The immunoregulatory role of NK cells in suppressing colitis in a murine CD4+
T cell transfer model was found to be dependent on perforin, suggesting that the NK cells were directly killing autoreactive T cells or some other intermediate effector cells such as DCs [69
]. In addition, several studies have shown that NK cells are potentially able to influence the subsequent adaptive immune response by lysing immature DCs [74
] or developing T cells [77
]. Therefore, it appears that NK cells may employ several different mechanisms to regulate the responses of other immune cells and thereby affect the development of autoimmunity.
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. Experimental autoimmune myasthenia gravis (EAMG) is an antibody-mediated autoimmune disease in which autoantibodies against the acetylcholine receptor (AchR) in neuromuscular junctions are stimulated in susceptible mice by repeated immunizations with Torpedo
AChR in adjuvant. Depletion of NK cells before immunization resulted in significantly delayed onset and decreased severity of EAMG with decreased anti-AChR antibody production [78
]. Interestingly, NK cell depletion after the initial immunization had no impact on the development of EAMG. In a mouse model of asthma, initial immunization with ovalbumin in adjuvant followed by repeated daily exposure to aerosolized ovalbumin resulted in CD4+
T cell-dependent pulmonary eosinophilic inflammation and systemic IgE production, consistent with a Th2 immune response [79
]. Depletion of NK cells before the initial immunization but not later during the challenge period resulted in a diminished infiltration of pulmonary eosinophils and CD3+
T cells as well as a decreased systemic production of IgE, suggesting a role for NK cells in promoting allergen-induced airway inflammation [79
]. Interestingly, the temporal impact of NK depletion observed in these models has also been reported in an EAE model in which the depletion of NK cells after the primary immunization did not impact development of EAE [72
]. These results suggest that NK cells may be most influential at the initiation of the autoimmune response.
In addition to potential immunoregulatory roles for NK cells in autoimmunity, NK cell-mediated cytotoxicity may result directly in significant organ-specific damage (Fig. ). Several groups have shown that activated NK cells can lyse autologous neurons in vitro
, suggesting that NK cell cytotoxity may have a role in EAE [80
]. NK cells have also been implicated in the selective neuronal death in the superior cervical ganglia of rats treated with guanethidine [82
]. Recent experiments have shown that NK cells can kill syngeneic dorsal root ganglia neurons by a perforin-dependent mechanism [83
]. Interestingly, it was shown that this response was mediated by NKG2D recognition of a ligand on dorsal root ganglia neurons that was not expressed on resistant central nervous system-derived neurons [83
]. NK cell-mediated killing of syngeneic neurons expressing an NK cell activation receptor ligand supports the hypothesis that inappropriate killing of self tissues by NK cells may reflect a loss of NK cell 'tolerance' occurring in tissues that have inappropriately downregulated MHC class I ligands for NK cell inhibitory receptors or that have aberrant expression of ligands for NK cell activation receptors or expression of these ligands in tissues that are normally isolated from NK cells.
NK cells appear to participate in mediating organ-specific damage in several murine models of autoimmunity. Experimental autoimmune uveoretinitis (EAU) is induced by immunizing sensitive strains of mice with ocular autoantigens. Depletion of NK cells before immunization resulted in significantly less severe EAU, demonstrating that NK cells participate in the development of EAU, either by directly mediating cellular damage or by supporting rather than suppressing autoreactive T cells [84
]. A murine model of autoimmune-mediated diabetes after viral infection with CVB4 provides another example of organ-specific, NK cell-mediated damage [85
]. In this model, mice whose pancreatic beta cells express a transgene for the suppressor of cytokine signaling (SOCS-1), an inhibitor of interferon signaling, develop diabetes soon after CVB4 infection. However, depletion of NK cells before infection with CVB4 prevented the development of diabetes, implying that NK cells contributed to the destruction of the infected pancreatic beta cells, although no direct evidence was presented to show the involvement of NK cell-mediated cytotoxicity [85
]. Therefore, in spite of in vitro
data suggesting that NK cell-mediated cytotoxicity may result in organ-specific autoimmunity, more direct in vivo
experimental evidence in murine models is needed to support this hypothesis.