Murine T cell development begins with the generation of a unique Vγ5(+)Vδ1(+) epidermal γδ T cell compartment and a unique, more broadly distributed Vγ6(+)Vδ1(+) subset that is an important source of interleukin-17 (IL-17). This study showed that these respective functional programs were determined by Skint-1, a thymic epithelial cell determinant. By engaging Skint-1(+) cells, Vγ5(+)Vδ1(+) thymocytes induced an Egr3-mediated pathway, provoking differentiation and the potential to produce IFN-γ while suppressing the γδ T cell lineage factor, Sox13, and a RORγt transcription factor-associated IL-17-producing capacity. Hence, the functions of the earliest T cells are substantially preprogrammed in the thymus. Additionally, the phenotype of Skint-1-selected fetal thymocytes permitted identification in the adult thymus of an analogous gene regulatory network regulated by the γδ T cell receptor. Hence, these observations describe a molecular pathway by which distinct stress-responsive lymphocyte repertoires may emerge throughout ontogeny and offer parallels with emerging perspectives on the functional selection of other lymphoid cells.
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