MHC class I-specific inhibitory receptors and their ligands structure diverse human NK-cell repertoires toward a balance of missing self-response

Blood. 2008 Sep 15;112(6):2369-80. doi: 10.1182/blood-2008-03-143727. Epub 2008 Jun 26.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Genotype
  • Histocompatibility Antigens Class I / immunology*
  • Humans
  • Killer Cells, Natural / immunology*
  • Ligands
  • Male
  • Middle Aged
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, Immunologic / analysis*
  • Receptors, KIR / analysis
  • Receptors, KIR / classification
  • Receptors, KIR / genetics
  • Receptors, KIR / immunology*
  • Receptors, Natural Killer Cell
  • Self Tolerance / immunology*

Substances

  • Histocompatibility Antigens Class I
  • KLRC1 protein, human
  • Ligands
  • NK Cell Lectin-Like Receptor Subfamily C
  • Receptors, Immunologic
  • Receptors, KIR
  • Receptors, Natural Killer Cell