ThPOK induction by gdTCR signaling promotes gd maturation (36.68)

Abstract

Abstract Current models suggest that the transcription factor ThPOK, the “master regulator” of CD4 commitment, is selectively induced in developing abTCR+ thymocytes by strong/persistent TCR signals, although direct evidence for this conjecture is lacking. We show that strong TCR signals mediated by antibody treatment or high affinity endogenous ligands cause ThPOK induction in thymocytes of the distinct gd T cell lineage. A key ThPOK cis-acting element, the distal regulatory element (DRE), is sufficient to mediate TCR dependent gene activation in gd thymocytes. Additionally, we demonstrate that ThPOK controls maturation and repertoire selection of developing gd thymocytes. Thus, lack of functional ThPOK causes a severe reduction in mature gdTCR+ thymocytes and a shift in Vg usage, while constitutive ThPOK expression leads to a striking increase in mature gd thymocytes. These results demonstrate that ThPOK expression in gd thymocytes is regulated by the strength of TCR signaling, define an important new role for ThPOK in gd T cell development/maturation, and lend strong support to the view that development of most gd T cells depends on TCR engagement/signaling.