Whereas the role of KIR expression by CTLs is suggested mostly by genetic reports and studies performed on peripheral blood lymphocytes (Martin et al. 2002; Momot et al. 2004; Namekawa et al. 2000; Snyder et al. 2003; Yen et al. 2001), there is now strong, converging evidence indicating that NKG2D and CD94/NKG2 receptors play essential roles in the control of effector CTLs in tissues, controlling important disease processes. The presence of abundant melanoma-specific CTLs in patients with progressive tumor has been correlated with expression of inhibitory NKG2A, suggesting that tumors can escape rejection by inducing and engaging inhibitory NKRs (Speiser et al. 1999). Conversely, several studies provide evidence for a role of activating CD94/NKG2 and NKG2D receptors in organ-specific autoimmunity. In rheumatoid arthritis patients, NKG2D was found to be induced on au-toreactive CD4 T cells in joint fluid whereas MIC was expressed on synovial cells. High IL-15 expression by synovial cells prevented the downregulation of NKG2D on engagement with molecules, hence sustaining chronic NKG2D activation (Groh et al. 2003). In NOD mice with type I diabetes, islet cells expressed NKG2D ligands and NKG2D function was critical for their destruction by autoreactive CTLs (Ogasawara et al. 2004). In celiac disease patients, activating CD94 receptors are highly upregulated in intraepithelial CTLs (Jabri et al. 2000 and manuscript in preparation) and high expression of IL-15 and MIC by intestinal epithelial cells appeared to prime their killing by intraep-ithelial CTLs through a TCR-independent, NKG2D-mediated pathway (Hue et al. 2004; Meresse et al. 2004). Altogether, these studies suggest the following model (Fig. 4). Exogenous stress (gluten in celiac disease or viral infection) or endogenous stress (type I diabetes) induces expression of IL-15 and nonclas-sic MHC class I molecules by tissue cells, initiating a feedback loop resulting in the arming of activating NKRs on CTLs and aberrant tissue destruction. The role of activating NKRs could be to lower the TCR activation threshold for cross-reactive self-antigen or to confer LAK properties against target cells expressing stress markers.
Importantly, the arming of NKG2D is restricted to cytolytic function. NKG2D cannot induce CTLs to secrete cytokines or proliferate, even on IL-15
Stressed cells my /mrreawcf TCR nspon&a to (satl}antlgen&
Fig. 4 Tissue control of CTL effector functions by NKG2D and IL-15. NKG2D ligands and IL-15 are expressed by tissue cells in stress and infectious conditions. IL-15 arms the NKG2D cytolytic signaling pathway in effector CTLs, focusing cytolytic activity on tissue targets undergoing stress and infection. This regulation is beneficial for host defense but may also lead to chronic autoimmune and inflammatory disorders stimulation (Groh et al. 2001; Roberts et al. 2001). Thus NKG2D alone does not explain how CTLs can undergo expansion and secrete IFN-y in celiac disease. The recent discovery that CTLs could also express CD94/NKG2C/DAP12 immunoreceptor complexes under pathological conditions suggests that another, more severe level of dysregulation occurs in some situations (Guma et al. 2004; Ortega et al. 2004). Ultimately, the loss of TCR control over proliferation might be involved in the malignant transformation of CTLs, as observed in celiac disease (reviewed in Green and Jabri 2003) or in IL-15-overexpressing mice (Fehniger et al. 2001).
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