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Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4+ T cell identity and function
Nature Immunology ( IF 27.7 ) Pub Date : 2021-07-26 , DOI: 10.1038/s41590-021-00980-8
Jayati Basu 1 , Bernardo S Reis 2 , Suraj Peri 3 , Jikun Zha 1 , Xiang Hua 1 , Lu Ge 1 , Kyle Ferchen 4 , Emmanuelle Nicolas 1 , Philip Czyzewicz 1 , Kathy Q Cai 5 , Yinfei Tan 6 , Juan I Fuxman Bass 7 , Albertha J M Walhout 7 , H Leighton Grimes 4 , Sergei I Grivennikov 8, 9 , Daniel Mucida 2 , Dietmar J Kappes 1
Affiliation  

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 (SilThPOK). In the present study, we describe a new autoregulatory loop whereby ThPOK binds to the SilThPOK 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 (Treg) cell gene expression signature. This promotes selective differentiation of naive CD4 T cells into GITRloPD-1loCD25lo (Triplelo) Treg 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.



中文翻译:

ThPOK 自动调节环在维持成熟 CD4+ T 细胞特性和功能中的重要作用

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。

更新日期:2021-07-26
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