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

Abstract

<p id="P1">Naive CD4 ⁺ T cells can be converted to Foxp3 ⁺ T regulatory cells (Tregs) in the periphery (iTregs), where induction of <i>Foxp3</i> gene expression is central to Treg differentiation. OX40 signaling is known to inhibit <i>Foxp3</i> expression and Treg induction, but the underlying mechanisms remain poorly defined. Here, we found that OX40 costimulation activates two distinct molecular pathways to suppress <i>Foxp3</i> 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 phos-phorylation 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. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/e1ac265e-671c-4d0b-bf18-f3d594e83f83/PubMedCentral/image/nihms-1502984-f0001.jpg"/> </div> </p><p id="P3">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. </p>