Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in transplant recipients. Long-term protective immunity against HCMV requires both sustained specific T-cell response and neutralizing IgG production, but the interplay between these effector arms remains poorly defined. We previously demonstrated that ␥␦ T cells play a substantial role as anti-HCMV Tcell effectors. The observation that CD16 (Fc␥RIIIA) was specifically expressed by the majority of HCMV-induced ␥␦ T cells prompted us to investigate their cooperation with anti-HCMV IgG. We found that CD16 could stimulate ␥␦ T cells independently of T-cell receptor (TCR) engagement and provide them with an intrinsic antibody-dependent cell-mediated cytotoxic ( IntroductionHuman cytomegalovirus (HCMV) is a widespread herpesvirus with an average seroprevalence of around 50% that increases with age and low socioeconomic status. Primary HCMV infection in an immunocompetent host is asymptomatic, but the virus establishes lifelong latency probably associated with periodic reactivation episodes. Conversely, damaging clinical symptoms can be observed in the course of HCMV infection in fetuses, neonates, and immunocompromised patients, such as those infected with HIV, recipients of solid organ allografts, or undergoing allogeneic hematopoietic stem cell transplantation. Constant immune surveillance is thus critical to keep the virus in check, and actually HCMV is highly immunogenic and elicits all the arsenal of the host immune defense. 1 The early events associated with virus entry into host cells first trigger a robust production of type I IFN and inflammatory cytokines, such as IL12, which are critical for the recruitment and activation of innate immune cells, particularly phagocytic leukocytes. 2 The activated innate immune cells then initiate the development of a vigorous adaptive immune response that culminates with the production of neutralizing antiviral antibodies (Abs) and IFN␥-producing and/or cytotoxic CD8 T cells. Both of these effectors are required for the establishment of long-lasting immunity against HCMV reactivation, superinfection, and congenital infection, but the cooperation between humoral immunity and T-cell effectors remains to be clarified.Humoral response against HCMV is characterized by the production of neutralizing Abs directed against viral envelope glycoproteins (mostly gB and gH) and gene products of the UL131A-128 locus, which are involved in virus attachment and entry into host cells. 3 However, the majority (90%) of HCMVspecific Abs do not have virus-neutralizing activity. 4 Such Abs could cooperate with cell effectors expressing CD16, the low affinity Fc receptor for IgG (FcR␥IIIa), to generate an Abdependent cell-mediated cytotoxicity (ADCC). However, ADCC would require that Abs are directed against HCMV-infected cells, something that has never been reported. Natural killer (NK) cells are usually considered as the main effector of ADCC, but evidence for a role of this process in immune defense again...

We evaluated the impact of cytomegalovirus (CMV)-induced immune responses, autoimmune-induced immune responses, and microbial translocation on immune activation in 191 human immunodeficiency virus type 1-infected patients from the ANRS CO3 Aquitaine Cohort. All enrolled subjects had achieved long-term virological suppression during receipt of combination antiretroviral therapy (cART). HLA-DR(+)/CD38(+) expression was 16.8% among CD8(+) T cells. Independent of age, CD4(+) T-cell count, 16S ribosomal DNA load, and regulatory T-cell count, positive results of Quantiferon CMV analysis (P = .02), positive results of CMV-pp65 enzyme-linked immunosorbent spot analysis (P = .01), positive results of CMV-pp65-specific CD8(+) T-cell analysis (P = .05), and CMV seropositivity (P = .01) were associated with a higher percentage of CD8+ T cells that expressed HLA-DR+/CD38+. Autoimmune response and microbial translocation were not associated with immune activation. Therefore, the CMV-induced immune response seems to be associated with chronic immune activation in cART recipients with sustained virological suppression.

Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large gd T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive gd T cells express the Fcgreceptor CD16, suggesting that gd T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16 pos gd T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating gd T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced gd T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced gd T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.