ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

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.

Automated summary

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.