Parallel Expansion of Human Virus-Specific FoxP3− Effector Memory and De Novo-Generated FoxP3+ Regulatory CD8+ T Cells upon Antigen Recognition In Vitro

Abstract

Although FoxP3 has been shown to be the most specific marker for regulatory CD4+ T cells, its significance in the CD8+ T cell population is not well understood. In this study, we show that the in vitro stimulation of human PBMC with hepatitis C virus or Flu virus-specific peptides gives rise to two distinct Ag-specific T cell populations: FoxP3− and FoxP3+CD8+ T cells. The FoxP3+ virus-specific CD8+ T cells share phenotypical markers of regulatory T cells, such as CTLA-4 and glucocorticoid-induced TNFR family-related gene, and do produce moderate amounts of IFN-γ but not IL-2 or IL-10. IL-2 and IL-10 are critical cytokines, however, because the expansion of virus-specific FoxP3+CD8+ T cells is blocked by IL-2- or IL-10-neutralizing mAbs. The virus-specific FoxP3+CD8+ T cells have a reduced proliferative capacity, indicating anergy, and display a cell-cell contact-dependent suppressive activity. Taken together, our results indicate that stimulation with a defined viral Ag leads to the expansion of two different cell populations: FoxP3− memory/effector as well as FoxP3+ regulatory virus-specific CD8+ T cells.