ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage

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Abstract
The transcription factor ThPOK is required for CD4+ T cell differentiation. Groups led by Taniuchi, Bosselut and Littman define distinct functions for ThPOK and other transcription factors in commitment versus specification of the CD4+ T cell lineage. The transcription factor ThPOK is required and sufficient for the generation of CD4+CD8− thymocytes, yet the mechanism by which ThPOK orchestrates differentiation into the CD4+ helper T cell lineage remains unclear. Here we used reporter mice to track the expression of transcription factors in developing thymocytes. Distal promoter–driven expression of the gene encoding the transcription factor Runx3 was restricted to major histocompatibility complex (MHC) class I–selected thymocytes. In ThPOK-deficient mice, such expression was derepressed in MHC class II–selected thymocytes, which contributed to their redirection to the CD8+ T cell lineage. In the absence of both ThPOK and Runx, redirection was prevented and cells potentially belonging to the CD4+ lineage, presumably specified independently of ThPOK, were generated. Our results suggest that MHC class II–selected thymocytes are directed toward the CD4+ lineage independently of ThPOK but require ThPOK to prevent Runx-dependent differentiation toward the CD8+ lineage.