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

Abstract

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.

Keywords: Cell-mediated immunity; Human cytomegalovirus; Regulatory T cells.