Divergence in the requirements for HEB factors in the generation and function of fetal-derived versus adult-derived γδ T cells (HEM2P.245)

Abstract

Abstract Gamma-delta (γδ) T cells are involved in mucosal immunity, wound healing, and tumor immunosurveillance. γδ T cells are programmed in the thymus to produce either IL-17 or IFNγ, but the molecular basis of this programming is not well understood. Here we show that mice lacking the E protein transcription factor HEB are defective in their ability to generate Vγ4 γδ T cells in fetal thymic organ culture. Since the HEB null allele is embryonic lethal, we generated mice lacking HEB only in hematopoietic cells by crossing HEBfl/fl mice with Vav-Cre mice (HEBfl/fl;vav-cre). These mice show a partial block in αβ T cell development, as seen in the fetal thymus of HEB-/- mice. In stark contrast to fetal gd T cells, however, the frequency of Vγ4 γδ T cells in the thymus of the HEBfl/fl;vav-cre mice is the equivalent to that in the WT thymus. Nonetheless, there is a skewing toward the CD27+ γδ T cells and away from CCR6+ γδ T cells, in both Vγ4+ and Vγ4- populations, suggesting a biased programming towards an IFNγ producing fate and away from the IL-17 producing fate. Moreover, there is a selective expansion of CD27+ Vγ4+ γδ T cells in the spleen, at the expense of other γδ T cell subsets, and a loss of CCR6+ Vγ4 γδ T cells in the lungs of HEBfl/fl;vav-cre mice. These results reveal that fetal Vγ4 cells are HEB-dependent, while adult Vγ4 cells appear to not require HEB, and strongly suggests that HEB is required for the generation and/or maintenance of IL-17 producing γδ T cells.