Human Tumor Antigen-Specific Helper and Regulatory T Cells Share Common Epitope Specificity but Exhibit Distinct T Cell Repertoire

CD4(+) regulatory T cells (Tregs) accumulate at tumor sites and play a critical role in the suppression of immune responses against tumor cells. In this study, we show that two immunodominant epitopes derived from the tumor Ags (TAs) NY-ESO-1 and TRAG-3 stimulate both CD4(+) Th cells and Tregs. TA-specific Tregs inhibit the proliferation of allogenic T cells, act in a cell-tocell contact dependent fashion and require activation to suppress IL-2 secretion by T cells. TRAG-3 and NY-ESO-1-specific Tregs exhibit either a Th1-, a Th2-, or a Th0-type cytokine profile and dot not produce IL-10 or TGF-beta. The Foxp3 levels vary from one Treg clone to another and are significantly lower than those of CD4(+) CD25(high) Tregs. In contrast to NY-ESO-1-specific Th cells, the NY-ESO-1-specific and TRAG-3-specific Treg clonotypes share a common TCR CDR3 V beta usage with Foxp3(+)CD4(+)CD25(high) and CD4(+)CD25(-) T cells and were not detectable in PBLs of other melanoma patients and of healthy donors, suggesting that their recruitment occurs through the peripheral conversion of CD4(+)CD25(-) T cells upon chronic Ag exposure. Collectively, our findings demonstrate that the same epitopes spontaneously stimulate both Th cells and Tregs in patients with advanced melanoma. They also suggest that TA-specific Treg expansion may be better impaired by therapies aimed at depleting CD4(+)CD25(high) Tregs and preventing the peripheral conversion of CD4(+)CD25(-) T cells. The Journal of Immunology, 2010, 184: 6709-6718.