Cutting edge: OX40 inhibits TGF-beta- and antigen-driven conversion of naive CD4 T cells into CD25+Foxp3+ T cells.

Naive CD4 T cells can develop into regulatory T cells by acquiring the transcription factor Foxp3. Combined signals from the TCR, CD28, IL-2R, and TGF-beta R promote Foxp3 expression in activated naive CD25(-) CD4 T cells. Here we show that OX40 (CD134) signaling inhibits TGF-beta-driven Foxp3 mRNA and suppresses the conversion of naive Ag-specific transgenic CD4 T cells into CD25(+)Foxp3(+) T cells. These data identify OX40 as a negative regulator of Foxp3 and suggest that OX40 can concomitantly promote effector T cell generation while antagonizing the differentiation of adaptive Foxp3(+) regulatory T cells.