Human Cytomegalovirus-specific regulatory and effector T cells are clonally identical

The majority of thymically arised regulatory CD4+CD25high T cells (Treg) show high affinity to self-antigens. It has been proposed that T-cell receptors (TCR) on Treg cells in the periphery also recognize foreign-antigens from pathogens, such as bacteria and viruses. Studies in mice have shown that peripheral Treg cells can be generated not only from naïve T cells but also from effector T cells (Teff). However, in humans the clonal TCR-repertoire of these Treg populations and their relation to effector CD4+CD25low Teff is not sufficiently known up to date. Here, we analyzed human TCRs derived from expanded Treg and Teff cells with defined specificity to MHC class-II restricted " foreign " epitopes of Cytomegalovirus (CMV). Remarkably, we found that both functionally distinct subsets share the same dominant TCR-CDR3 clones in vitro. In contrast to their Teff counterparts, the Treg cells express low CD127 and IL-2, but high IL-10 upon antigen stimulation. Therefore, together with increased FOXP3 expression, but incomplete foxp3 DNA-demethylation, human CMV-antigen specific Treg cells exhibit an induced phenotype (iTreg) in vitro with similarity to recently described Tr-1 phenotype. Moreover, the clonal identity was confirmed in freshly isolated CD4+CD25low and CD4+CD25high subsets, suggesting their generation occurred already in vivo. Peripheral CD25high Treg cells suppress the anti-viral immune response in patients with frequent CMV-reactivations, implying their development as reaction on chronic antigen-exposure. Our results demonstrate directly for the first time, that the same human T-cell clone can possess the phenotype of Teff and Treg cells with specificity to identical foreign epitopes and suggest that Treg-induction in the periphery is supported by frequent antigen-exposure.