The induction of FoxP3 in naive T cells is dependent upon the transcription factors TFE3 and TFEB. (163.4)

Abstract TFE3 and TFEB are members of the basic helix-loop-helix leucine zipper MiTF/TFE (Microphthalmia-associated transcription factor) family of transcription factors. They are ubiquitously expressed in human and murine tissue and form homo- and/or heterodimers to bind the E-box core sequence CAYGTG. Using a transgenic mouse line expressing a trans dominant negative (TDN) inhibitor of TFE3 and TFEB in T cells, we previously showed that CD40L is a key target of both TFE3 and TFEB and that inactivating these molecules causes hyper IgM syndrome. Unexpectedly, we now show that naïve T cells from these mice have a significant defect in the in vitro differentiation into the inducible T regulatory (iTreg) phenotype, demonstrated by reduced induction of the hallmark Treg transcription factor, FoxP3. Although Smad7, a negative regulator of TGFβ signaling, is a target gene of TFE3 in non-lymphoid cells, preliminary results indicate its expression is unaffected in these cells, as is the phosphorylation of Smad3, indicating TGFβ signaling pathway is intact. This suggests TFE3/B are important in Treg differentiation, possibly as direct regulators of the FoxP3 gene. This combined evidence demonstrates a multiplicity of roles for TFE3 and TFEB in T cell function.