期刊
CELL REPORTS
卷 36, 期 8, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2021.109602
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资金
- NIH [K08-CA191019-01A1, 1DP2AI136599-01]
- Skin Cancer Foundation
- Leukemia Research Foundation
- Doris Duke Charitable Foundation
- Damon Runyon Foundation (DRCRF) [CI-84-16, 2016095]
- DDCF CRM Award
- Northwestern University Flow Cytometry Core Facility - Cancer Center Support Grant (NCI) [CA060553]
Inappropriate CD4(+) T cell differentiation can affect immune response and autoimmune diseases. The study identified a key role for Zinc finger E-box-binding homeobox (ZEB1) in regulating autoimmune inflammation, particularly through inhibition of JAK-STAT signaling. ZEB1 and JAK2 downregulation reduces pathogenic cytokine expression in T cells from MS patients, suggesting a potential targetable mechanism for regulating disease-related inflammation.
Inappropriate CD4(+) T helper (Th) differentiation can compromise host immunity or promote autoimmune disease. To identify disease-relevant regulators of T cell fate, we examined mutations that modify risk for multiple sclerosis (MS), a canonical organ-specific autoimmune disease. This analysis identified a role for Zinc finger E-box-binding homeobox (ZEB1). Deletion of ZEB1 protects against experimental autoimmune encephalitis (EAE), a mouse model of multiple sclerosis (MS). Mechanistically, ZEB1 in CD4(+) T cells is required for pathogenic Th1 and Th17 differentiation. Genomic analyses of paired human and mouse expression data elucidated an unexpected role for ZEB1 in JAK-STAT signaling. ZEB1 inhibits miR-101-3p that represses JAK2 expression, STAT3/STAT4 phosphorylation, and subsequent expression of interleukin-17 (IL-17) and interferon gamma (IFN-gamma). Underscoring its clinical relevance, ZEB1 and JAK2 downregulation decreases pathogenic cytokines expression in T cells from MS patients. Moreover, a Food and Drug Administration (FDA)-approved JAK2 inhibitor is effective in EAE. Collectively, these findings identify a conserved, potentially targetable mechanism regulating disease-relevant inflammation.
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