Cytomegalovirus infection in HIV-infected and uninfected individuals is characterized by circulating regulatory T cells of unconstrained antigenic specificity

Abstract

Cytomegalovirus (CMV) infection is associated with immune-suppression in immune-compromised hosts and old adults. We previously showed that ex vivo CMV restimulation of peripheral blood mononuclear cells (PBMC) of CMV-seropositive volunteers expanded CD4+CD27-CD28- regulatory T cells (Tregs). Here we evaluate the phenotype and function of circulating CD4+CD27-CD28- T cells of CMV-seropositive adults. Compared with CMV-seronegative, CMV-seropositive adults had 10-fold higher CD4+CD27-CD28-% T cells in PBMC. Circulating CD4+CD27-CD28- T cells from both CMV-seropositive and seronegative donors expressed higher levels of TGFβ, granzyme B, CD39, CD147 and IL-35, and lower levels of CD127, compared with their parent circulating CD4+ T cells. However, only CMV-seropositive circulating CD4+CD27-CD28- had increased FOXP3 expression. CD4+CD27-CD28- sorted from the PBMC of CMV-seropositive donors expanded ex vivo in the presence of rhIL2 and inhibited ex vivo proliferation of autologous PBMC restimulated with CMV, varicella-zoster virus or C. albicans antigens. CD4+CD27-CD28- sorted from CMV-seronegative PBMC did not expand in the presence of rhIL2 and did not inhibit autologous PBMC proliferation. CD3+CD27-CD28- circulating T cells (≥80% CD8+) from CMV-seropositive HIV-infected donors also inhibited ex vivo proliferation of autologous PBMC restimulated with CMV or HIV. These data indicate that CMV-seropositive individuals have circulating Tregs that inhibit cell-mediated immune responses to CMV and other antigens and may be contribute to an immune-suppressive effect of CMV infection. Moreover, the phenotypic similarity between circulating CD4+CD27-CD28- Tregs with differentiated effector T cells suggests that the two T-cell subsets might evolve in parallel or in sequence from the same progenitor cells in response to CMV stimulation during reactivations.

Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells

“…These cells are thought to accumulate with repeated antigen exposure and therefore expand over time in CMV + individuals (Pourgheysari et al, 2007). These cells may play an active role in immunosuppression in an antigenindependent manner, as demonstrated recently (Tovar-Salazar and Weinberg, 2017). Therefore, we assessed the T cell populations in our cohorts to determine if these cells were associated with the reduction in vaccine responses in CMV + individuals.…”

A new clustering method identifies multiple sclerosis‐specific T‐cell receptors

“…CMV infection has been reported to increase Treg numbers, which downregulate immune responses 23,24 . Therefore, we measured the percentage of Tregs in CD4 + T cells (Treg%) in our participants, using the gating strategy shown in Fig.…”

“…Treg% was decreased in MS patients in the present study, in accordance with a previous study, 49 but was partially restored in CMV‐IgG‐positive, HLA‐DRB1*04:05 ‐positive MS patients. CMV infection induces Tregs that downregulate CMV‐specific as well as nonspecific immune responses in CMV‐infected humans and in a mouse model 23,24,50 . It is therefore possible that CMV infection protects against disability progression by counteracting the decrease in Tregs inherent to MS 49 .…”

Impact of Historic Migrations and Evolutionary Processes on Human Immunity

“…(PBMC) in response to cytomegalovirus infection in vitro [58]. In one study, patients with chronic hepatitis C virus (HCV) infection and hepatitis A virus (HAV) superinfection presented lower titers of HCV RNA than patients harboring only HCV, suggesting that HCV replication might be potentially suppressed during HAV infection [59], although this will still require further investigation.…”