HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells.

Abstract

Natural killer (NK) ceUs recognize alloantigens on normal cels. One of these alloantigens correlates with homozygosity for a dimorphism of HLA-C at positions 77-80, which is shared by a number ofHLA-C alleles. A second alleic alloantigen correlates with homozygosity for the alternative HLA-C dimorphism, which is shared by the remaning HLA-C alleles. Moreover, NK1-and NK2-specific NK ceUl lines can be generated by mixed leukocyte cultures in which donor and stimulator are homozygous for the alternative dimorphisms at positions 77-80 of HLA-C. In the present work, the role of HLA-C in NK ceUl-mediated allorecognition was directly investigated by analyzing the effects produced by transfection of several HL4-C alleles on NK sensitivity of class I-deleted mutant ceUl lines. Transfection of ceUs with HLA-C aleles encoding Asn-77-Lys-80 (including HLA-Cw4, -CwS, and -Cw6) inhibited the lysis of the targets by NK1-specifilc NK cells, whereas HLA-C alleles encoding Ser-77-Asn-80 (including HLA-Cwl, -Cw7, and -Cw13) protected the targets from NK2-specific NK ceUls. Thus, HLA-C alleles are the dominant inhibitory ligands that protect targets from lysis by these allospecific NK cels.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Initial studies indicated a simple bipartite system in which KIR2DL2/3 recognizes HLA‐C allotypes with asparagine at residue 80 (the HLA‐C1 motif), and KIR2DL1 recognizes HLA‐C allotypes with lysine at residue 80 (the HLA‐C2 motif). Dimorphism at residue 44 of the KIR molecule causes these specificity differences, where KIR2DL2/3 has lysine and KIR2DL1 has methionine 36, 100, 104, 105. Crystal structures showed that K44 of KIR2DL2 forms a hydrogen bond with the N80 of HLA‐C1 99.…”

Receptor systems controlling natural killer cell function are genetically stratified in Europe

“…6 The HLA-C1 allotype, characterized by having asparagine at position 80, binds KIR 2DL2/3/2DS2. 7,8 The HLA-C2 allotype, characterized by lysine at position 80, is a ligand for 2DL1/S1. 7,8 Polymorphism within the HLA-B gene produces either Bw4 or Bw6 allotypes, the former of which are ligands for 3DL1 and possibly 3DS1.…”

“…7,8 The HLA-C2 allotype, characterized by lysine at position 80, is a ligand for 2DL1/S1. 7,8 Polymorphism within the HLA-B gene produces either Bw4 or Bw6 allotypes, the former of which are ligands for 3DL1 and possibly 3DS1. 9 Given the inherent complexity of both KIR and their HLA class I ligands and the fact that they segregate independently on different chromosomes, these cell surface molecules need to be considered together for functional interactions to be appreciated.…”

Combination of KIR and HLA gene variants augments the risk of developing birdshot chorioretinopathy in HLA-A*29-positive individuals

“…KIR2DL2 and 2DL3 bind a subset of HLA-C allotypes containing an asparagine at amino-acid position 80 of the heavy chain (HLA-C1 alleles) and KIR2DL1 binds the remaining HLA-C allotypes with lysine 80 (HLA-C2 alleles). [19][20][21] KIR3DL1 binds 40% of the HLA-B allotypes containing a serologically defined Bw4 epitope 22,23 and KIR3DL2 binds HLA-A3/A11. 24,25 The strength of these interactions is highly sensitive to polymorphism of the KIR and HLA genes, as well as the HLA-bound peptide sequence.…”