title: Relationship of NKG2C Copy Number with the Distribution of Distinct Cytomegalovirus-Induced Adaptive NK Cell Subsets.
abstract: CD94/NKG2C and lack of FcεRγ (FcRγ) expression are considered markers of the adaptive NK cell response to human CMV (HCMV) infection. Despite the fact that FcRγ(-) and NKG2C(bright) NK cells share some phenotypic, epigenetic, and functional features, their relationship remains unclear. To address this issue, a systematic analysis of NKG2C(bright) and FcRγ expression was carried out in NK cells from a cohort of healthy young adults (n = 81) considering NKG2C copy number, previously related to the magnitude of NKG2C(+) NK cell expansion. NKG2C(bright) and FcRγ(-) NK cells coincided in a subgroup of HCMV(+) individuals, pointing to a common host-virus interaction pattern. Even though FcRγ loss was often confined to expanded NKG2C(bright) NK cells, both markers appeared occasionally dissociated, consistent with the existence of distinct adaptive NK cell subsets. Remarkably, FcRγ loss was mostly accumulated within the NKG2C(bright) subset in NKG2C(+/+) subjects, whereas NKG2C(-)FcRγ(-) NK cell subpopulations were more frequently detected in NKG2C(+/del) donors and also in NKG2C(del) (/del) individuals, independently of activating killer Ig-like receptor expression. The distribution of other NK receptors (i.e., killer Ig-like receptor, LILRB1, or CD57) supported a sequential differentiation from NKG2C(bright)FcRγ(+) to NKG2C(bright)FcRγ(-) NK cells. Noticeably, NKG2C(bright) NK cells produced more TNF-α in response to Ab-dependent activation, regardless of their FcRγ levels. Moreover, the TNF-α response of NKG2C(-)FcRγ(-) subpopulations was lower than that of concurrent NKG2C(bright)FcRγ(-) NK cells, further supporting that FcRγ levels and enhanced potential for cytokine production are uncoupled. Overall, our data extend the characterization of adaptive NK cell subsets that differentiate in response to HCMV, supporting a relationship between their distribution and NKG2C copy number.
authors.affiliation: Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain; amuntasell@imim.es lbotet@imim.es.
authors.forename: Aura
authors.identifier: 0000-0003-2894-0486
authors.initials: A
authors.lastname: Muntasell
authors.affiliation: Universitat Pompeu Fabra, Barcelona 08002, Spain; and.
authors.forename: Aldi
authors.identifier: 0000-0001-5897-165X
authors.initials: A
authors.lastname: Pupuleku
authors.affiliation: Instituto de Investigación Sanitaria Puerta de Hierro, Majadahonda 28222, Spain.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cisneros
authors.affiliation: Universitat Pompeu Fabra, Barcelona 08002, Spain; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Vera
authors.affiliation: Instituto de Investigación Sanitaria Puerta de Hierro, Majadahonda 28222, Spain.
authors.forename: Manuela
authors.initials: M
authors.lastname: Moraru
authors.affiliation: Instituto de Investigación Sanitaria Puerta de Hierro, Majadahonda 28222, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Vilches
authors.affiliation: Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain; Universitat Pompeu Fabra, Barcelona 08002, Spain; and amuntasell@imim.es lbotet@imim.es.
authors.forename: Miguel
authors.identifier: 0000-0003-4882-065X
authors.initials: M
authors.lastname: López-Botet
mesh_terms: D056704:Adaptive Immunity; D000328:Adult; D049109:Cell Proliferation; D002478:Cells, Cultured; D015331:Cohort Studies; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D005260:Female; D018628:Gene Dosage; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000821:virology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000821:virology; D008297:Male; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000235:genetics / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C527059:KLRC2 protein, human; D055654:NK Cell Lectin-Like Receptor Subfamily C; D017452:Receptors, IgG; D014409:Tumor Necrosis Factor-alpha