HEB plays a critical role in the installment of IL-17 program in fetal thymic γδ T cells (HEM2P.231)

Abstract

Abstract IL-17 producing γδ T cells that arise during fetal development form an integral part of the immune system of various lymphoid and mucosal tissues in mice. Here we aim to better understand the transcriptional networks that drive the functional programming of IL-17 producing γδ T cells. Specifically, we investigated the role of the transcription factor HEB in this process using mice that carry the HEB null allele. To evaluate the role of HEB in fetal γδ T cell development, we utilized fetal thymic organ culture from HEB+/+ and HEB-/- embryos at E14. We found that the absence of HEB did not have a significant impact on γδ T cell numbers, and that all functional subsets of γδ T cells were present as indicated by expression of CCR6, CD27, CD44 and CD62L. However, the fetal thymic γδ T cells from HEB knockout mice exhibited a profound deficiency in their ability to produce IL-17, especially in the CD44+ γδ T cell population. In addition, HEB-deficient fetal γδ T cells expressed significantly lower levels of SOX13 and RORγt, factors associated with IL-17 producing γδ T cells, while expression of IFNγ, Tbet and Egr3 were unchanged. Furthermore, HEB conditional knockout mice on a Vav-Cre background had significantly lower frequencies of IL-17 producing γδ T cells in the spleen, lymph nodes and lungs. Collectively, our work shows for the first time that HEB plays an important role in installing the IL-17 program in γδ T cells.