CD4(+) helper and CD8(+) cytotoxic T cells, two major subsets of αβTCR expressing lymphocytes, are differentiated from common precursor CD4(+)CD8(+) double-positive (DP) thymocytes. Bifurcation of the CD4(+)/CD8(+) lineages in the thymus is a multilayered process and is thought to culminate in a loss of developmental plasticity between these functional subsets. Advances in the last decade have deepened our understanding of the transcription control mechanisms governing CD4 versus CD8 lineage commitment. Reciprocal expression and antagonistic interplay between two transcription factors, ThPOK and Runx3, is crucial for driving thymocyte decisions between these two cell fates. Here, we first focus on the regulation of ThPOK expression and its role in directing helper T cell development. We then discuss a novel aspect of the ThPOK/Runx3 axis in modifying CD4(+) T cell function upon exposure to gut microenvironment.
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