Paired inhibitory and triggering NK cell receptors for HLA class I molecules

Human natural killer (NK) cells specifically interact with major histocompa tibility complex (MHC) class I molecules employing different receptor syste ms, shared with subsets of alpha beta and gamma delta T lymphocytes. Killer cell immunoglobulin-like receptors (KIRs) recognize groups of human leukoc yte antigen (HLA) class Ia proteins displaying common structural features a t the alpha-1 domain; among them, KIR2DL4 has been proposed to specifically interact with the class Ib molecule HLA-G1. Members of a related family of immunoglobulin (Ig)-like receptors (ILT2 or LIR-1 and ILT4 or LIR-2), expr essed by other leukocyte lineages, interact with a broad spectrum of class Ia molecules and HLA-G1. On the other hand, CD94/NKG2-A(-C) and NKG2D lecti n-like receptors, respectively, recognize the class Ib molecules HLA-E and MICA. A recurrent finding within the different receptor families is the exi stence of pairs of homologous molecules that often share the same ligands b ut display divergent functions. Inhibitory receptors rend to exhibit an aff inity for HLA molecules higher than their activating counterparts. Recruitm ent of SH2 domain-bearing tyrosine phosphatases (SHP) by cytoplasmic phosph orylated immunoreceptor tyrosine-based inhibition motifs (ITIMs) is a cruci al event for the inhibitory signalling pathway. By contrast, triggering rec eptors assemble with homodimers of immune tyrosine-based activation motif ( ITAM)-bearing adaptor molecules (i.e., DAP12, CD3 zeta) that engage tyrosin e kinases (ZAP70 and syk). Human Immunology 61, 7-17 (2000). (C) American S ociety for Histocompatibility and Immunogenetics, 2000. Published by Elsevi er Science Inc.