Long-term expansion of effector/memory Vδ2− γδ T cells is a specific blood signature of CMV infection

Abstract

The ability of human ␥␦ T cells to develop immunologic memory is still a matter of debate. We previously demonstrated the involvement of V␦2 ؊ ␥␦ T lymphocytes in the response of immunosuppressed organ recipients to cytomegalovirus (CMV). Here, we demonstrate their ability to mount an adaptive immune response to CMV in immunocompetent subjects. V␦2 ؊ ␥␦ T-cell peripheral blood numbers, repertoire restriction, and cytotoxicity against CMV-infected fibroblasts were markedly increased in CMV-seropositive, compared with CMV-seronegative, healthy persons. Whereas V␦2 ؊ ␥␦ T cells were found as naive cells in CMV ؊ patients, they virtually all exhibited the cytotoxic effector/ memory phenotype in CMV ؉ patients, which is also observed in transplanted patients challenged with CMV. This longterm complete remodeling of the V␦2 ؊ ␥␦ T-cell population by CMV predicts their ability to exhibit an adaptive anti-CMV immune response. Consistent with this, we observed that the secondary response to CMV was associated with a faster ␥␦ T-cell expansion and a better resolution of infection than the primary response. In conclusion, the increased level of effectormemory V␦2 ؊ IntroductionHuman cytomegalovirus (CMV) is a widespread ␤-herpesvirus that establishes a lifelong viral persistence without detectable symptoms in immunocompetent patients but with life-threatening consequences in immunologically immature or compromised patients. Many studies have been reported that support an important role for adaptive T lymphocytes in the control of CMV infection. [1][2][3][4] In addition, we have demonstrated that the ␥␦ T-cell subpopulation contributes to the anti-CMV immune responses. 5,6 These unconventional T cells are generally considered to be intermediates between innate and adaptive immunity because of their rapid and massive responses to very diverse immune challenges.Compelling data exist that demonstrate the importance of ␥␦ T cells in various microbial infections in humans. They exhibit in vitro reactivity against cells infected by viruses, bacteria, or parasites and are selectively expanded in the peripheral blood of infected patients. [7][8][9][10] The majority of human circulating ␥␦ T cells express a T-cell receptor (TCR) encoded by the V␥9 and V␦2 gene segments. These cells are activated after interaction with nonpeptidic phosphorylated compounds, collectively called phosphoantigens, which are metabolic intermediates of the isoprenoid biosynthetic pathway. 11,12 These phosphoantigens are expressed by a variety of bacteria and parasites and are also present in some tumors. The other ␥␦ T cells are known as V␦2 Ϫ ␥␦ T cells, are largely located in mucosal epithelia and in the spleen, and represent approximately 20% of all circulating ␥␦ T cells. These cells predominantly express a TCR containing the V␦1 region. Their repertoire in the peripheral blood of most healthy adults is restricted, whereas it is polyclonal in the thymus and in cord blood. [13][14][15] This observation suggests that unknown environmental factors encou...

The pentameric complex of human Cytomegalovirus: cell tropism, virus dissemination, immune response and vaccine development

“…11) in SOTR [128][129][130] and in immune-competent subjects [131] as well as in foetuses with congenital infection [132]. This expansion has been interpreted as a type of specific signature of the adaptive immune response to HCMV infection [133]. Following expansion, g/d T cells were found to be able to kill HCMV-infected target cells in vitro [134], and CD16 (FcgRIIIA) was found to be specifically expressed by the majority of HCMV-induced g/d T cells.…”

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants

“…After CMV infection, but not after other viral infections (e.g. herpes simplex virus, Varicella zoster virus, Epstein-Barr virus and influenza), Vd2 neg cd T cells undergo massive expansion in the blood of kidney transplant recipients (KTRs) (14,17). Recently, we demonstrated that Vd2 neg cd T cell expansion in the peripheral blood of KTRs was associated with the resolution of infection, and we observed a higher risk of recurrence at the end of a curative treatment in the absence of Vd2 neg cd T cell expansion (18).…”

TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance

“…Primary gd T-cell lines (Vd1, Vd1C3, Vd5) and Vd2 neg gd T-cell clones (Vg8Vd3, Vg2Vd3) were generated and cultured following the same methods as described previously. 14,35 For co-culture functional assays and IFNg secretion, primary T-cell lines and clones (5 £ 10 4 cells per well) were incubated with monolayers of tumor cell lines or HUVECs that were uninfected or infected with the human CMV clinical strain TB40-E as described. 35 After 24 h at 37 C, supernatants were isolated by centrifugation, and cytokine secretion (IFNg and TNFa) was measured by ELISA.…”

“…11 Interestingly, AICD seems to be reduced for epithelial Vd2 neg gd T cells, and increasing evidence supports an important role of this subset for tumor and infection immunosurveillance. 12 Human Vd2 neg gd T cells expand in the periphery of individuals during CMV infection in various pathophysiological contexts, including solid-organ and stem cell transplantation, [13][14][15][16][17] where they develop cytotoxic function and produce proinflammatory cytokines such as tumor necrosis factor a (TNFa) and IFNg. 18 Importantly, CMV-induced expansion of Vd2 neg gd T cells correlates with decreased susceptibility to post-transplant cancers, suggesting a role in tumor immunosurveillance in vivo.…”