Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4⁺ T cell identity and function

The transcription factor ThPOK (encoded by the Zbtb7b gene) controls homeostasis and differentiation of mature helper T cells, while opposing their differentiation to CD4⁺ intraepithelial lymphocytes (IELs) in the intestinal mucosa. Thus CD4 IEL differentiation requires ThPOK transcriptional repression via reactivation of the ThPOK transcriptional silencer element (Sil^ThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the Sil^ThPOK to maintain its own long-term expression in CD4 T cells. Disruption of this loop in vivo prevents persistent ThPOK expression, leads to genome-wide changes in chromatin accessibility and derepresses the colonic regulatory T (T_reg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITR^loPD-1^loCD25^lo (Triple^lo) T_reg cells and conversion to CD4⁺ IELs in the gut, thereby providing dominant protection from colitis. Hence, the ThPOK autoregulatory loop represents a key mechanism to physiologically control ThPOK expression and T cell differentiation in the gut, with potential therapeutic relevance.