Parallel in vitro expansion of human hepatitis C virus specific FoxP3- effector memory and FoxP3+ regulatory CD8+ T cells on recognition of the same antigen

Abstract

There is growing consensus that regulatory T cells contribute to regulation of T cell responses to tumors and microbes. FoxP3 has been shown to be the most specific marker for regulatory CD4+ T cells, however, itrsquor;s significance in the CD8+ T cell population is less understood. Here we show that the in vitro stimulation of PBMC from chronically HCV infected patients with specific peptides gives rise to two distinct antigen-specific T 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 GITRI expression. They do not produce Interleukin (IL)–2 or IL–10, but moderate amounts of IFNg after peptide specific stimulation and have a suppressive, cell-contact dependent suppressive activity. Interleukin (IL)–2 and IL–10 are critical cytokines since the expansion of virus-specific FoxP3+ CD8+ T cells is blocked by the addition of anti-IL–2- or IL–10- neutralizing monoclonal antibodies. Taken together, our results indicate that stimulation with the same viral antigen leads to the expansion of both, FoxP3- memory/ effector as well as FoxP3+ regulatory virus-specific CD8+ T cells that regulate immune responses antigen-specifically. These results may also have therapeutic consequences since the antigen-specific induction of regulatory CD8+ T cells may be used to achieve a fine tuning of antigen-specific suppression in various clinical settings.