Deconstructing the KIR–HLA complex

Abstract

1 Boyington, J.C. et al. (2000) Crystal Structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand. Nature 405, 537–5432 Tormo, J. et al. (2000) Crystal structure of a lectin-like natural killer receptor bound to its MHC class I ligand. Nature 402, 623–6313 Natarajan, K. et al. (1999) Interaction of the NK cell inhibitory receptor Ly49A with H-2Dd: identification of a site distinct from the TCR site. Immunity 11, 591–601When major histocompatibility complex (MHC) class I molecules present foreign peptides to cytotoxic CD8+ T cells, the T cells are activated to kill the target cells. Natural killer (NK) cells also have receptors that interact with MHC class I molecules, but interaction with class I/self-peptides generates an inhibitory signal that prevents NK cell lysis of the target cell. Thus, NK cells do not kill normal, healthy class I-expressing cells, but do kill cells that express inadequate levels of class I, such as cancer cells. Inhibitory receptors on NK cells belong to two families – the immunoglobulin (Ig) superfamily (called killer inhibitory receptors, KIR), and the C-type lectin superfamily (called Ly49 receptors). Human inhibitory NK receptors can be of either type, whereas mice only have Ly49 receptors.Now, Boyington et al. report the first crystal structure of a KIR (KIR2DL2) in complex with its class I ligand (HLA-Cw3)1. The structure reveals that dimeric KIR binds across the top of the α1 and α2 helices of HLA-Cw3, and interacts with amino acids at positions 7 and 8 of the peptide. This interaction is similar to that between the T-cell receptor (TCR) and MHC class I. However, the TCR binds centrally across the groove whereas the KIR binds at one end of the groove, with an area of overlap in-between. For NK T cells, this overlap suggests that it is unlikely that a TCR and a KIR on the same NK cell can simultaneously interact with a single MHC class I molecule.The KIR2DL2/HLA-Cw3 interaction is very different to the interaction between the murine dimeric receptor Ly49A and its class I ligand H-2Dd, which was described recently2,3. In this case, a single Ly49 molecule binds at one side of the peptide-binding groove. Although Ly49 does not interact directly with the peptide, the peptide must fill the groove for the Ly49A/H-2Dd interaction to occur.These studies provide the first structural information on the interaction between NK inhibitory receptors and MHC class I ligands. Further studies are required to address the role of zinc ions in KIR/HLA interactions, and to determine how KIR variants that induce NK cell lysis interact with class I molecules.