Submitted March 7, 2008
Accepted June 10, 2008
MHC class I-specific inhibitory receptors and their ligands structure diverse human NK cell repertoires towards a balance of missing-self response
Makoto Yawata*, Nobuyo Yawata, Monia Draghi, Fotini Partheniou, Ann-Margaret Little, and Peter Parham
Structural Biology, Stanford University School of Medicine, Stanford, CA, United States
Histocompatibility Laboratories, The Anthony Nolan Trust, London, United Kingdom
Haematology, The Royal Free Hospital, London, United Kingdom
* Corresponding author; email: myawata{at}stanford.edu.
Variegated expression of six inhibitory HLA class I-specific receptors on primary NK cells was studied using high-dimension flow cytometry in 58 human individuals to understand the structure and function of NK cell repertoires. Sixty-four subsets expressing all possible receptor combinations were present in each repertoire and the frequency of receptor-null cells varied amongst 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 which 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, five types of NK cell repertoire were defined by their content of NKG2A+/NKG2A- cells, frequency of receptor-null cells, and degree of KIR receptor co-expression. The analyses provide new perspective on how personalized human NK cell repertoires are structured.
