Understanding the mechanism of action of cytomegalovirus-induced regulatory T cells.

We previously showed that CMV-induced CD4+CD27-CD28- T cells have regulatory (Treg) function. Here we sought to identify the target/s and the mechanistic underpinning/s of this effect. CMV-induced CD4+CD27-CD28-were sorted from CMV-stimulated PBMC and added to CMV-stimulated autologous PBMC cultures. Transwell experiments showed that the CMV-induced Treg mechanism of action required cell-to-cell contact. CMV-Treg significantly decreased proliferation of autologous CMV-stimulated CD8+ and, to a lesser extent, CD4+ T cells; reduced activation and increased apoptosis of CD4+ and CD8+ T cells; and increased apoptosis and expression of CTLA-4, T cell-inhibitory ligand, on dendritic cells. There was no effect on monocytes. Anti-PD-1, but not anti-CTLA-4, mAb-treatment increased proliferation of CD8+ T cells and decreased apoptosis of CD4+ and CD8+ T cells. Our data indicated that CD8+ T cells were the main target of CMV-specific Treg, which induced apoptosis of their targets using the PD-1 pathway.