HEB collaborates with TCR signaling to upregulate <i>Id3</i> and enable γδT17 cell maturation in the fetal thymus.

Abstract

T cells expressing the γδ T cell receptor (TCR) develop in a stepwise process initiating at the αβ/γδ T cell branch point, followed by maturation and acquisition of effector functions, including the ability to produce interleukin-17 (IL-17) as γδT17 cells. Previous studies linked TCR signal strength and fate choices to the transcriptional regulator HEB (<i>Tcf12</i>) and its antagonist, Id3, but how these factors regulate different stages of γδ T cell development has not been determined. We found that immature fetal γδTCR⁺ cells from conditional <i>Tcf12</i> knockout (HEB cKO) mice were defective in activating the γδT17 program at an early stage, whereas <i>Id3</i>-deficient (Id3-KO) mice displayed a partial block in γδT17 maturation and a defect in IL-17 production. We also found that HEB cKO mice failed to upregulate <i>Id3</i> during γδT17 development, whereas HEB overexpression elevated the levels of <i>Id3</i> in collaboration with TCR signaling. Moreover, Egr2 and HEB were bound to several of the same regulatory sites on the <i>Id3</i> gene locus in the context of early T cell development. Therefore, our findings reveal an interlinked sequence of events during which HEB and TCR signaling synergize to upregulate <i>Id3</i>, which enables maturation and acquisition of the γδT17 effector program.