DIVERGENT FUNCTIONS OF LECTIN-LIKE RECEPTORS ON NK CELLS

NK cells express a superfamily of surface proteins that share a common structure: dimeric type II integral membrane proteins whose extracell ular domains have structural features of C-type (calcium-dependent) le ctins. These receptors are encoded in a single genetic region called t he NK complex (NKC). The NKC encompasses several families of genes, in cluding Ly-49 (in mice and rats), NKR-P1 (in mice, rats, and humans), NKG2 (in humans and rats), and CD94 (in humans). Different NKC recepto rs have been shown to activate or to inhibit NR function, and differen t receptors within the same family can have opposing functions. In thi s review, we discuss the molecular pathways by which NK cells are acti vated, and the mechanisms by which inhibitory receptors interrupt acti vation. By studying the inhibitory receptor Ly-49A, we have demonstrat ed that inhibition utilizes the cytoplasmic phosphatase, SHP-1, which binds to a motif in the receptor cytoplasmic domain, termed an immunor eceptor tyrosine-based inhibitory motif (ITIM). In this regard, the le ctin-like receptors are functionally similar to the immunoglobulin-lik e killer inhibitory receptors (KIRs) on human NK cells. The presence o f an ITIM generally correlates with inhibitory activity among NKC lect in-like receptors, as demonstrated by the human NKG2 receptor family L anier and his colleagues have recently shown that NKG2 receptors can f orm heterodimers with the invariant lectin-like receptor CD94. Selecti ve association of CD94 with different NKG2 receptors may explain funct ional differences for CD94 in different NK clones.