KIR2DL4

Abstract: Cytotoxicity by natural killer (NK) cells is inhibited by major histocompatibility complex (MHC) class I molecules on target cells. This inhibition may be mediated by NK receptors with different MHC specificities. A family of four NK-specific complementary DNAs (cDNAs), designated NKATs (NK-associated transcripts), was identified that encoded related transmembrane proteins, characterized by an extracellular region with two or three immunoglobulin-superfamily domains and by a cytoplasmic domain with an unusual antigen receptor activation motif (ARAM). The distribution of these cDNAs was clonotypic and correlated with NK cell inhibition by particular class I alleles. Thus, NKAT cDNAs may encode receptors for class I molecules on NK cells.

Abstract: Human natural killer (NK) cells express several killer cell immunoglobulin (Ig)-like receptors (KIRs) that inhibit their cytotoxicity upon recognition of human histocompatibility leukocyte antigen (HLA) class I molecules on target cells. Additional members of the KIR family, including some that deliver activation signals, have unknown ligand specificity and function. One such KIR, denoted KIR2DL4, is structurally divergent from other KIRs in the configuration of its two extracellular Ig domains and of its transmembrane and cytoplasmic domains. Here we show that recombinant soluble KIR2DL4 binds to cells expressing HLA-G but not to cells expressing other HLA class I molecules. Unlike other HLA class I–specific KIRs, which are clonally distributed on NK cells, KIR2DL4 is expressed at the surface of all NK cells. Furthermore, functional transfer of KIR2DL4 into the cell line NK-92 resulted in inhibition of lysis of target cells that express HLA-G, but not target cells that express other class I molecules including HLA-E. Therefore, given that HLA-G expression is restricted to fetal trophoblast cells, KIR2DL4 may provide important signals to maternal NK decidual cells that interact with trophoblast cells at the maternal–fetal interface during pregnancy.