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Basu J , Reis BS , Peri S , Zha J , Hua X , Ge L , Ferchen K , Nicolas E , Czyzewicz P , Cai KQ , Tan Y , Fuxman Bass JI , Walhout AJM , Grimes HL , Grivennikov SI , Mucida D , Kappes DJ
Essential role of a ThPOK autoregulatory loop in the maintenance of mature CD4(+) T cell identity and function
Nat Immunol. 2021 Aug;22(8) :969-982
PMID: 34312548   
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Abstract
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.
Notes
1529-2916 Basu, Jayati Reis, Bernardo S Orcid: 0000-0002-6841-116x Peri, Suraj Zha, Jikun Hua, Xiang Ge, Lu Ferchen, Kyle Nicolas, Emmanuelle Czyzewicz, Philip Cai, Kathy Q Tan, Yinfei Fuxman Bass, Juan I Walhout, Albertha J M Grimes, H Leighton Orcid: 0000-0001-8162-6758 Grivennikov, Sergei I Mucida, Daniel Orcid: 0000-0002-0000-0452 Kappes, Dietmar J Orcid: 0000-0002-9112-509x AI068907/U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)/ GM10717/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ GM082971/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)/ CA218133/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ CA006927/U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)/ Journal Article United States Nat Immunol. 2021 Aug;22(8):969-982. doi: 10.1038/s41590-021-00980-8. Epub 2021 Jul 26.