CMV infection is characterized by high of frequencies of CD27−CD28− T cells. Here we demonstrate that CMV-specific CD4+CD27−CD28− cells are regulatory T cells (TR). CD4+CD27−CD28− cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose dependent fashion. Compared with the entire CMV-stimulated CD4+ T-cell population, higher proportions of CD4+CD27−CD28− TR expressed FoxP3, TGFβ, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, FasL and GITRL. CMV-CD4+CD27−CD28− TR expanded in response to IL-2, but not to CMV antigenic re-stimulation. The anti-proliferative effect of CMV-CD4+CD27−CD28− TR significantly decreased after granzyme B or TGFβ inhibition. The CMV-CD4+CD27−CD28− TR of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4+CD27−CD28− TR. The CMV-CD4+CD27−CD28− TR may contribute to the down-regulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.
Protection against zoster conferred by zoster vaccine live (ZVL; Zostavax™) wanes over time. We compared the cell-mediated immunity (VZV-CMI) of adults ≥70 years who received a second dose of ZVL ≥10 years after the initial dose with de novo-immunized age-matched controls. Before and during the first year after vaccination, VZV-CMI was significantly higher in re-immunized compared with the de novo vaccinees. At 3 years, VZV-CMI differences between groups decreased and only memory responses remained marginally higher in re-immunized participants. In conclusion, the increase in VZV-CMI generated by re-immunization with ZVL is at least equally persistent compared with de novo immunization.
Older age is associated with increased infectious morbidity and decreased immune responses to vaccines, but the mechanisms that mediate this effect are incompletely understood. The efficacy and immunogenicity of the live attenuated zoster vaccine (ZVL) have a very-well-described negative association with the age of the vaccinee. In a study of 600 ZVL recipients 50 to Ͼ80 years of age, we investigated immunological factors that might explain the effect of age on the immunogenicity of ZVL. Using FluoroSpot assays and flow cytometry, we determined that varicella-zoster virus (VZV)-specific peak T helper 1 (VZV-Th1) responses to ZVL were independently predicted by prevaccination VZV-Th1 responses, regulatory T cells (Treg), and PD1-expressing immune checkpoint T cells (Tcheck) but not by the age of the vaccinee. Persistence of VZV-Th1 1 year after vaccination was independently predicted by the factors mentioned above, by peak VZV-Th1 responses to ZVL, and by the age of the vaccinee. We further demonstrated by ex vivo blocking experiments the mechanistic role of PD1 and CTLA4 as modulators of decreased VZV-Th1 responses in the study participants. VZV-specific cytotoxic T cell (VZV-CTL) and T follicular helper responses to ZVL did not correlate with age, but similar to other Th1 responses, VZV-CTL peak and baseline responses were independently correlated. These data expand our understanding of the factors affecting the magnitude and kinetics of T cell responses to ZVL in older adults and show the importance of prevaccination Treg and Tcheck in modulating the immunogenicity of ZVL. This presents new potential interventions to increase vaccine responses in older adults. IMPORTANCE Vaccination is the most effective method to protect older adults against viral infections. However, the immunogenicity of viral vaccines in older adults is notoriously poor. The live attenuated zoster vaccine (ZVL) provides the best example of a gradual decrease of vaccine immunogenicity with every 10year age increase above 50 years. Here we show that the abundance of regulatory T cells before vaccine administration to older adults has a significant inhibitory effect on immune responses to ZVL and, together with baseline immunity to varicella-zoster virus, explains the effect of age on the immunogenicity of ZVL. Moreover, in vitro blockade of regulatory T cell mechanisms of action with biologic modulators restores immune responses to varicella-zoster virus in vaccinees. Collectively, these observations suggest that immune modulators that block regulatory T cell activity may increase responses to viral attenuated vaccines in older adults. MJ. 2019.The effect of age on the immunogenicity of the live attenuated zoster vaccine is predicted by baseline regulatory T cells and varicellazoster virus-specific T cell immunity. J Virol A ging is associated with a decline in multiple components of the immune system (termed immune senescence) (1). This is clinically apparent from the increases in the frequency and severity of common infections with increasi...
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