title: Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry.
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.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Horowitz
authors.forename: Dara M
authors.initials: DM
authors.lastname: Strauss-Albee
authors.forename: Michael
authors.initials: M
authors.lastname: Leipold
authors.forename: Jessica
authors.initials: J
authors.lastname: Kubo
authors.forename: Neda
authors.initials: N
authors.lastname: Nemat-Gorgani
authors.forename: Ozge C
authors.initials: OC
authors.lastname: Dogan
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.forename: Sally
authors.initials: S
authors.lastname: Mackey
authors.forename: Holden
authors.initials: H
authors.lastname: Maecker
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.forename: Manisha
authors.initials: M
authors.lastname: Desai
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Blish
mesh_terms: D000328:Adult; D016000:Cluster Analysis; D004777:Environment; D005260:Female; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D008875:Middle Aged; D010641:Phenotype; D055607:Receptors, Natural Killer Cell / Q000235:genetics*; D055815:Young Adult
chemical_list: D015395:Histocompatibility Antigens Class I; D055607:Receptors, Natural Killer Cell