ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Yuan Qian, Gabriel Arellano, Igal Ifergan, Jean Lin, Caroline Snowden, Taehyeung Kim, Jane Joy Thomas, Calvin Law, Tianxia Guan, Roumen D. Balabanov, Susan M. Kaech, Stephen D. Miller*, Jaehyuk Choi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


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-γ). 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.

Original languageEnglish (US)
Article number109602
JournalCell reports
Issue number8
StatePublished - Aug 24 2021


  • T cell differentiation
  • T helper cells
  • autoimmunity
  • immunogenetics
  • micro-RNA
  • multiple sclerosis
  • single-cell RNA-seq
  • transcription factor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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