Cutting edge: OX40 inhibits TGF-β- 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-βR promote Foxp3 expression in activated naive CD25^- CD4 T cells. Here we show that OX40 (CD134) signaling inhibits TGF-β-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.