The CD94/NKG2C+ NK-cell subset on the edge of innate and adaptive immunity to human cytomegalovirus infection

• HCMV infection promotes a variable and persistent expansion of NKG2Cbright NK-cells.
• This NK-cell subset displays distinctive phenotypic and functional features.
• The effect is observed in healthy donors and in pathological conditions.
• NKG2Cbright NK-cells respond poorly to infected cells but efficiently mediate ADCC.
• The underlying cellular and molecular mechanisms remain unknown.

Human cytomegalovirus (HCMV) causes a highly prevalent and lifelong infection, with a multifaceted impact in human health. NK cells play an important role in the immune response to HCMV and the virus has reciprocally developed a variety of immune evasion strategies. We originally reported that HCMV infection promotes, to a variable degree in healthy individuals, a redistribution of the NK-cell receptor (NKR) repertoire which persists under steady-state conditions. Its hallmark is an expansion of a mature NK-cell subset displaying high surface levels of the CD94/NKG2C activating receptor, with additional distinctive phenotypic and functional features. Such adaptation of host NK cells to HCMV infection, confirmed in different clinical settings, is particularly magnified in immunocompromised patients and influenced by NKG2C gene copy number. The mechanism(s) underlying the differentiation and proliferation of NKG2C+ NK cells, the basis for the individual differences in the magnitude of their expansion, and their precise role in anti-viral defence remain open issues. Moreover, the possibility that the impact of HCMV infection on the NK-cell compartment may exert a broader influence on immunity deserves further attention.