HEB is required for the specification of fetal IL-17-producing γδ T cells

IL-17-producing γδ T (γδT17) cells are critical components of the innate immune system. However, the gene networks that control their development are unclear. Here we show that HEB (HeLa E-box binding protein, encoded by Tcf12 ) is required for the generation of a newly defined subset of fetal-derived CD73 − γδT17 cells. HEB is required in immature CD24 + CD73 − γδ T cells for the expression of Sox4 , Sox13 , and Rorc , and these genes are repressed by acute expression of the HEB antagonist Id3. HEB-deficiency also affects mature CD73 + γδ T cells, which are defective in RORγt expression and IL-17 production. Additionally, the fetal TCRγ chain repertoire is altered, and peripheral Vγ4 γδ T cells are mostly restricted to the IFNγ-producing phenotype in HEB-deficient mice. Therefore, our work identifies HEB-dependent pathways for the development of CD73 + and CD73 − γδT17 cells, and provides mechanistic evidence for control of the γδT17 gene network by HEB. The γδ T cell pool includes abundant IL-17-producing cells that protect mucosal surfaces, but the signals that control γδ T cell specification are unclear. Here the authors identify a role for the transcription factor HEB, and antagonistic activity of Id3, in the development of these cells.