OX40 Costimulation Inhibits Foxp3 Expression and Treg Induction via BATF3-Dependent and Independent Mechanisms

Naive CD4⁺ T cells can be converted to Foxp3⁺ T regulatory cells (Tregs) in the periphery (iTregs), where induction of Foxp3 gene expression is central to Treg differentiation. OX40 signaling is known to inhibit Foxp3 expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress Foxp3 expression in freshly activated naive CD4⁺ T cells. Specifically, OX40 upregulates BATF3 and BATF, which produce a closed chromatin configuration to repress Foxp3 expression in a Sirt1/7-dependent manner. Moreover, OX40 can also activate the AKT-mTOR pathway, especially in the absence of BATF3 and BATF, to inhibit Foxp3 induction, and this is mediated by phosphorylation and nuclear exclusion of the transcription factor Foxo1. Taken together, our results provide key mechanistic insights into how OX40 inhibits Foxp3 expression and Treg induction in the periphery. Zhang et al. show that OX40 inhibits Foxp3 expression by upregulating BATF and BATF3 expression in activating CD4⁺ T cells, and BATF proteins close the Foxp3 locus by recruiting the histone deacetylases Sirt1/7. Additionally, OX40 activates the AKT-mTOR pathway to inhibit Foxp3 expression in the absence of the BATF proteins.