Journal
NATURE IMMUNOLOGY
Volume 22, Issue 8, Pages 969-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41590-021-00980-8
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Funding
- NCI NIH HHS [R01 CA227629, R01 CA218133, T32 CA117846, P30 CA006927] Funding Source: Medline
- NIAID NIH HHS [R01 AI068907] Funding Source: Medline
- NIGMS NIH HHS [R35 GM122502, R01 GM082971, R01 GM107179] Funding Source: Medline
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The transcription factor ThPOK plays a critical role in the homeostasis and differentiation of mature helper T cells, controlling the expression of Sil(ThPOK) in CD4 T cells through an autoregulatory loop. Disruption of this loop leads to changes in chromatin accessibility and the derepression of colonic T-reg cell gene expression, promoting the differentiation of naive CD4 T cells into specific T-reg cells and CD4(+) IELs, providing protection from colitis in the gut. This autoregulatory loop represents a key mechanism for the physiological control of ThPOK expression and T cell differentiation in the gut with potential therapeutic relevance.
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. The transcription factor ThPOK is critical for homeostasis and differentiation of mature helper T cells. Here, Kappes and colleagues describe a ThPOK-mediated positive autoregulatory loop that is crucial for tissue-specific T-reg cell differentiation, maintenance of intestinal T-reg cell integrity and conversion of these cells into CD4(+) intraepithelial lymphocytes.
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