NK cells: tuned by peptide?

Summary Natural killer cells express multiple receptors for major histocompatibility complex ( MHC ) class I, including the killer cell immunoglobulin‐like receptors ( KIR s) and the C‐type lectin‐like CD 94: NKG 2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG 2 family of receptors parallels the conservation of MHC ‐E, the ligand for CD 94: NKG 2A/C/E. Binding of both CD 94: NKG 2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA ‐E binding non‐inhibitory peptides augment inhibition at CD 94: NKG 2A, while HLA ‐C binding non‐inhibitory peptides antagonize inhibition at KIR 2 DL 2/3, implying that KIR s are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIR s, such as KIR 2 DL 3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD 94: NKGA . Conversely, NKG 2A‐positive NK cells sense MHC class I downregulation more efficiently than KIR s. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.