MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response.
Variegated expression of 6 inhibitory HLA class I-specific receptors on primary NK cells was studied using high-dimension flow cytometry in 58 humans to understand the structure and function of NK-cell repertoires. Sixty-four subsets expressing all possible receptor com-binations were present in each repertoire, and the frequency of receptor-null cells varied among the donors. Enhancement in missing-self response between NK subsets varied substantially where subset responses were defined by donor KIR/HLA allotypes, reflecting the differences in interaction between inhibitory receptors and their ligands. This contrasted to the enhancement conferred by NKG2A, which was constant and of intermediate strength. We infer a mechanism that modulates frequencies of the NK subsets displaying diverse levels of missing-self response, a system that reduces the presence of KIR-expressing subsets that display either too strong or too weak a response and effectively replaces them with NKG2A-expressing cells in the repertoire. Through this high-resolution analysis of inhibitory receptor expression, 5 types of NK-cell repertoire were defined by their content of NKG2A(+)/NKG2A(-) cells, frequency of receptor-null cells, and degree of KIR receptor coexpression. The analyses provide new perspective on how personalized human NK-cell repertoires are structured.
Yawata
Makoto
M
Department of Structural Biology, Stanford University School of Medicine, CA 94305-5126, USA. myawata@stanford.edu
Yawata
Nobuyo
N
Draghi
Monia
M
Partheniou
Fotini
F
Little
Ann-Margaret
AM
Parham
Peter
P
D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D008297:Male; D008875:Middle Aged; D055654:NK Cell Lectin-Like Receptor Subfamily C; D011971:Receptors, Immunologic / Q000032:analysis*; D054340:Receptors, KIR / Q000032:analysis / Q000145:classification / Q000235:genetics / Q000276:immunology*; D055607:Receptors, Natural Killer Cell; D017634:Self Tolerance / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; C527054:KLRC1 protein, human; D008024:Ligands; D055654:NK Cell Lectin-Like Receptor Subfamily C; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell