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 extracellular domains have structural features of C-type (calcium-dependent) lectins. These receptors are encoded in a single genetic region called the NK complex (NKC). The NKC encompasses several families of genes, including Ly-49 (in mice and rats), NKR-P1 (in mice, rats, and humans). NKG2 (in humans and rats), and CD94 (in humans). Different NKC receptors have been shown to activate or to inhibit NK function, and different receptors within the same family can have opposing functions. In this review, we discuss the molecular pathways by which NK cells are activated, and the mechanisms by which inhibitory receptors interrupt activation. By studying the inhibitory receptor Ly-49A, we have demonstrated that inhibition utilizes the cytoplasmic phosphatase, SHP-1, which binds to a motif in the receptor cytoplasmic domain, termed an immunoreceptor tyrosine-based inhibitory motif (ITIM). In this regard, the lectin-like receptors are functionally similar to the immunoglobulin-like killer inhibitory receptors (KIRs) on human NK cells. The presence of an ITIM generally correlates with inhibitory activity among NKC lectin-like receptors, as demonstrated by the human NKG2 receptor family. Lanier and his colleagues have recently shown that NKG2 receptors can form heterodimers with the invariant lectin-like receptor CD94. Selective association of CD94 with different NKG2 receptors may explain functional differences for CD94 in different NK clones.