Human Cytomegalovirus Infection Is Associated with Increased Proportions of NK Cells That Express the CD94/NKG2C Receptor in Aviremic HIV‐1–Positive Patients

Abstract

In healthy blood donors, serological positivity for human cytomegalovirus (HCMV) is associated with an increased proportion of NK cells bearing the CD94/NKG2C NK cell receptor (NKR). The expression of the activating CD94/NKG2C NKR and of the inhibitory CD94/NKG2A NKR was studied in a cohort of 45 aviremic human immunodeficiency virus type 1 (HIV-1)-positive patients receiving highly active antiretroviral therapy. The proportions of NKG2C+ NK cells were significantly increased in HIV-1-positive patients (mean +/- SD, 25.9% +/- 23.0%), compared with those in 31 healthy individuals (mean +/- SD, 16.1% +/- 20.7%). Yet, the association vanished when HCMV serological status was considered in a multivariate regression model. These results support the conclusion that changes in the NKR repertoire in HIV1-positive patients are related to a concomitant HCMV infection.

IL‐12 and IL‐15 induce the expression of CXCR6 and CD49a on peripheral natural killer cells

“…This data also suggests cytokine signaling, in addition to CMV infection, can lead to expansion of NK cells expressing the adaptive marker NKG2C 22, 23, 24. This transition may be supported by changes at a transcription factor level, for example IL‐15 and TGFβ have recently been shown to induce transition of Eomes low to Eomes high NK cells 29.…”

“…Clonal expansion of NKG2C+ NK cells in the peripheral blood has been seen following viral infection, particularly cytomegalovirus infection (CMV) 22, 23, 24. Furthermore NK cells in mice and humans display adaptive behavior in response to a combination of pro‐inflammatory cytokines, interleukin (IL)‐12, IL‐15, and IL‐18 25, 26, 27.…”

Independent skewing of the T cell and NK cell compartments associated with cytomegalovirus infection suggests division of labor between innate and adaptive immunity

“…The effect of CMV on the NK compartment might, however, be different. Studies of HIV and hantavirus infections indicate that previous exposure to CMV might have a priming effect on the NKG2C + NK population leading to a more efficient expansion upon additional viral encounters (Bjorkstrom et al 2011;Guma et al 2006b). Also in patients infected with hepatitis B or C, expansion of NKG2C + NK cells seems to be dependent on CMV infection (Beziat et al 2012).…”

“…Intriguingly, recent evidence in mice suggest that NK cell responses to an array of chemical and viral antigens also involve adaptive immune features such as expansion and contraction of subpopulations of NK cells with specific and heightened responses to subsequent rechallenges with the same antigen (O' Leary et al 2006;Paust et al 2010;Sun et al 2009). In humans, such adaptive behavior has been observed in the context of both acute and latent CMV infection (Foley et al 2012;Guma et al 2006b;LopezVerges et al 2011). Thus, NK cells expressing the activating receptor NKG2C expand specifically during acute infection or viral reactivation in immunocompromised patients (Foley et al 2012;Kuijpers et al 2008;Lopez-Verges et al 2011).…”

Sweet Is the Memory of Past Troubles: NK Cells Remember

“…The expansion of CD94-NKG2C + NK cells has also been observed during other viral infections in humans, leading to the question: Can other viral infections lead to NK cell memory development in humans? Expansion of NK cells expressing CD94-NKG2C has been observed in individuals with chronic hepatitis B or hepatitis C virus (Béziat et al 2012), in aviremic HIV-1-infected patients (Gumá et al 2006), and in individuals following hantavirus infection (Björkström et al 2011). A transient expansion and persistent survival of NKG2C + CD57 + NK cells is also seen in individuals infected with chikungunya virus (Petitdemange et al 2011).…”