The killer cell immunoglobulin-like receptor (KIR) locus comprises a variable and rapidly evolving set of genes encoding multiple inhibitory and activating receptors. The activating receptors recently evolved from the inhibitory receptors and both bind HLA class I and probably also class I-like structures induced by viral infection. Although generally considered natural killer (NK) cell receptors, KIR are also expressed by a large fraction of effector memory T cells, which slowly accumulate during human life. These effector memory cells are functionally similar to NK cells, as they are immediate effector cells that are cytotoxic and produce IFN-γ. However, different rules apply to NK and T cells with respect to KIR expression and function. For example, KIR tend to modulate signals driven by the T-cell receptor (TCR) rather than to act independently, and use different signal transduction pathways to modulate only a subset of effector functions. The most important difference may lie in the rules governing tolerance: while NK cells with activating KIR binding self-HLA are hyporesponsive, the same is unlikely to apply to T cells. We argue that the expression of activating KIR on virus-specific T cells carrying TCR that weakly cross-react with autoantigens can unleash the autoreactive potential of these cells. This may be the case in rheumatoid arthritis, where cytomegalovirus-specific KIR2DS2(+) T cells might cause vasculitis. Thus, the rapid evolution of activating KIR may have allowed for efficient NK-cell control of viruses, but may also have increased the risk that slowly evolving T-cell responses to persistent pathogens derail into autoimmunity.
© 2010 The Authors. Immunology © 2010 Blackwell Publishing Ltd.