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.

转录因子 ThPOK（由Zbtb7b基因编码）控制成熟辅助 T 细胞的稳态和分化，同时反对它们分化为肠黏膜中的 CD4 ⁺上皮内淋巴细胞 (IEL)。因此，CD4 IEL 分化需要通过重新激活ThPOK转录沉默元件 (Sil ^{ThPOK ) 来抑制}ThPOK转录。在本研究中，我们描述了一个新的自动调节循环，其中 ThPOK 与 Sil ^ThPOK结合以维持其在 CD4 T 细胞中的长期表达。体内这个环的破坏阻止了持续的 ThPOK 表达，导致染色质可及性的全基因组变化，并抑制结肠调节性 T (T _reg ) 细胞基因表达特征。这促进幼稚 CD4 T 细胞选择性分化为 GITR ^lo PD-1 ^lo CD25 ^lo (Triple ^lo ) T _reg细胞并在肠道中转化为 CD4 ⁺ IEL，从而提供对结肠炎的主要保护。因此，ThPOK 自动调节环代表了生理控制肠道中 ThPOK 表达和 T 细胞分化的关键机制，具有潜在的治疗相关性。