Skint-1 Identifies a Common Molecular Mechanism for the Development of Interferon-γ-Secreting versus Interleukin-17-Secreting γδ T Cells

SummaryMurine 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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► Skint-1 selectively determines the functional phenotype of Vγ5Vδ1+ fetal thymocytes
► Skint-1 activates Egr3, which suppresses the development of Sox13+RORγt+ γδ-17 cells
► γδTCR engagement of adult thymocytes activates Egr3 and suppresses Sox13 and RORγt