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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 Vitro¹

University of Connecticut School of Medicine, Farmington Avenue, Farmington, CT 06030

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.

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