Genetic and Environmental Determinants of Human NK Cell Diversity Revealed by Mass Cytometry

Sci Transl Med. 2013 Oct 23;5(208):208ra145. doi: 10.1126/scitranslmed.3006702.

Abstract

Natural killer (NK) cells play critical roles in immune defense and reproduction, yet remain the most poorly understood major lymphocyte population. Because their activation is controlled by a variety of combinatorially expressed activating and inhibitory receptors, NK cell diversity and function are closely linked. To provide an unprecedented understanding of NK cell repertoire diversity, we used mass cytometry to simultaneously analyze 37 parameters, including 28 NK cell receptors, on peripheral blood NK cells from 5 sets of monozygotic twins and 12 unrelated donors of defined human leukocyte antigen (HLA) and killer cell immunoglobulin-like receptor (KIR) genotype. This analysis revealed a remarkable degree of NK cell diversity, with an estimated 6000 to 30,000 phenotypic populations within an individual and >100,000 phenotypes in the donor panel. Genetics largely determined inhibitory receptor expression, whereas activation receptor expression was heavily environmentally influenced. Therefore, NK cells may maintain self-tolerance through strictly regulated expression of inhibitory receptors while using adaptable expression patterns of activating and costimulatory receptors to respond to pathogens and tumors. These findings further suggest the possibility that discrete NK cell subpopulations could be harnessed for immunotherapeutic strategies in the settings of infection, reproduction, and transplantation.

Publication types

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

MeSH terms

  • Adult
  • Cluster Analysis
  • Environment*
  • Female
  • Gene Expression Regulation
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunologic Memory
  • Killer Cells, Natural / cytology*
  • Killer Cells, Natural / metabolism*
  • Male
  • Mass Spectrometry / methods*
  • Middle Aged
  • Phenotype
  • Receptors, Natural Killer Cell / genetics*
  • Young Adult

Substances

  • Histocompatibility Antigens Class I
  • Receptors, Natural Killer Cell