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Blood, 15 September 2008, Vol. 112, No. 6, pp. 2369-2380.
Prepublished online as a Blood First Edition Paper on June 26, 2008; DOI 10.1182/blood-2008-03-143727.
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IMMUNOBIOLOGY
MHC class I–specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response
Makoto Yawata1,*,
Nobuyo Yawata1,*,
Monia Draghi1,
Fotini Partheniou2,
Ann-Margaret Little2,3, and
Peter Parham1
1 Department of Structural Biology, Stanford University School of Medicine, CA;
2 Histocompatibility Laboratories, Anthony Nolan Trust, and
3 Department of Haematology, the Royal Free Hospital, London, United Kingdom
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.
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