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 lo PD-1 lo CD25 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.