Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 43, Issue 12, Pages 3268-3278Publisher
WILEY
DOI: 10.1002/eji.201343773
Keywords
CD94; NKG2C; Cytomegalovirus; Human; NK cells; NKG2C genotype
Categories
Funding
- Plan Nacional de I+D [SAF2010-22153-C03]
- EU SUDOE program [SOE2/P1/E341]
- Red HERACLES (Instituto de Salut Carlos III)
- Fundacio La Marato TV3 [121531]
- Asociacion Espanola Contra el Cancer (AECC)
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Human cytomegalovirus (HCMV) infection promotes a persistent expansion of a functionally competent NK-cell subset expressing the activating CD94/NKG2C receptor. Factors underlying the wide variability of this effect observed in HCMV-seropositive healthy individuals and exacerbated in immunocompromized patients are uncertain. A deletion of the NKG2C gene has been reported, and an apparent relation of NKG2C genotype with circulating NKG2C(+) NK-cell numbers was observed in HCMV+ children. We have assessed the influence of NKG2C gene dose on the NK-cell repertoire in a cohort of young healthy adults (N = 130, median age 19 years). Our results revealed a relation of NKG2C copy number with surface receptor levels and with NKG2C(+) NK-cell numbers in HCMV+ subjects, independently of HLA-E dimorphism. Functional studies showed quantitative differences in signaling (i.e. iCa(2+) influx), degranulation, and IL-15-dependent proliferation, in response to NKG2C engagement, between NK cells from NKG2C(+/+) and hemizygous subjects. These observations provide a mechanistic interpretation on the way the NKG2C genotype influences steady-state NKG2C(+) NK-cell numbers, further supporting an active involvement of the receptor in the HCMV-induced reconfiguration of the NK-cell compartment. The putative implications of NKG2C zygosity over viral control and other clinical variables deserve attention.
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