Antibody-dependent anti-cytomegalovirus activity of human γδ T cells expressing CD16 (FcγRIIIa)

Abstract

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...

Antibody-Mediated Response of NKG2Cbright NK Cells against Human Cytomegalovirus

“…In close resemblance, HCMVinduced gd T cells secrete IFN-g in response to IgG-opsonized virions (35). We previously reported that NK cells may directly sense HCMV through a TLR2-dependent mechanism (55).…”

“…CD16 + gd T cells have been shown to produce IFN-g when incubated with IgG-opsonized HCMV virions (35). We assessed whether NKG2C bright NK cells could also respond to viral particles in the presence of specific IgG.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…In liver transplantation, cd T cell genes were included in the gene expression signature of tolerant recipients (195), and intragraft cd T cell infiltration was associated with pediatric liver transplant tolerance (196). cd T cells have also been linked to allograft rejection by observations suggesting that cd T cells expressing the Fc-c receptor CD16 bind donor-specific antibodies and participate in allograft injury via ADCC (197). CMV-infected and immunized patients have increased numbers of cd T cells and higher levels of donor-specific antibodies (198).…”

Type I IFNs and IL-18 Regulate the Antiviral Response of Primary Human γδ T Cells against Dendritic Cells Infected with Dengue Virus

“…Alternatively, gd T cell lines also were used to study the cytotoxic response of Vg9Vd2 T cells to HSV-1 (17) to document noncytolytic antiviral activity and IFN-g production against severe acute respiratory syndrome virus (14), as well as Fas-Fas ligand-and perforin-granzyme B-dependent cytotoxicity against cells infected with influenza A virus (18). T cell lines also were used to study the IFN-g response of Vd2 2 gd T cells to fibroblasts infected with CMV (19). It was reported that the activation marker CD69 is upregulated on gd T cells during dengue infection (20).…”