Effect of CD4+CD25+ and CD4+CD25- T regulatory cells on the generation of cytolytic T cell response to a self but human tumor-associated epitope in vitro

CD4(+) T cells naturally expressing CD25 molecules (natural T regulatory cells (Tregs)) have a role in maintaining self tolerance and in regulating responses to infectious agents, transplantation Ags, and tumor Ags. CD4(+) Tregs induced from CD4(+)CD25(-) precursors (induced Tregs) also regulate immune responses in the periphery. However, which of these Tregs is a major impediment in generating antitumor CTL responses is not clear. We show that although the CD4(+)CD25(+) subsets isolated from peripheral blood-derived lymphocytes do suppress the proliferation of CD4(+)CD25(-) effector T cells, they do not suppress the activation and expansion of the self but melanoma-associated, melanoma Ag-reactive T cell 1 (MART-1)(27-35)-specific CD8(+) T cells stimulated by the respective peptide-loaded matured dendritic cells in vitro. The CD4+CD25- counterparts, in contrast, lead to the generation of CD25(+) glucocorticoid-inducible TNFR+-Forkhead/winged helix transcription factor(+) populations and efficiently suppress the activation and expansion of the MART-1(27-35) epitope-specific CTLs. Our data suggest that when CTL precursors are optimally stimulated, natural Tregs are not a formidable constraint toward generating a robust antitumor CTL response, but induced Tregs could be.