Regulatory function of cytomegalovirus-specific CD4+CD27−CD28− T cells

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, Fas-L and GITR-L. CMV-CD4+CD27−CD28− TR expanded in response to IL-2, but not to CMV antigenic restimulation. 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 downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.