ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Inappropriate CD4+ T helper (Th) cell differentiation contributes to autoimmune diseases like multiple sclerosis (MS).
• Identifying key regulators of T cell fate is crucial for understanding and treating autoimmune conditions.

Purpose of the Study:

• To investigate the role of Zinc finger E-box-binding homeobox 1 (ZEB1) in T cell differentiation and autoimmune disease pathogenesis.
• To elucidate the molecular mechanisms by which ZEB1 influences T cell responses and disease risk.

Main Methods:

• Examined mutations modifying multiple sclerosis (MS) risk to identify disease-relevant regulators.
• Utilized experimental autoimmune encephalitis (EAE) as a mouse model for MS.
• Performed genomic analyses of human and mouse expression data.
• Investigated the role of ZEB1 in CD4+ T cell differentiation, JAK-STAT signaling, and cytokine production.

Main Results:

• ZEB1 deletion protected against EAE, indicating a protective role.
• ZEB1 is essential for pathogenic Th1 and Th17 cell differentiation.
• ZEB1 inhibits miR-101-3p, which in turn represses JAK2 expression, leading to STAT3/STAT4 phosphorylation and increased IL-17 and IFN-γ production.
• Downregulation of ZEB1 and JAK2 reduced pathogenic cytokine expression in T cells from MS patients.
• A JAK2 inhibitor demonstrated efficacy in the EAE model.

Conclusions:

• ZEB1 is a critical regulator of pathogenic T helper cell differentiation and autoimmune inflammation.
• ZEB1 influences T cell fate through the JAK-STAT signaling pathway.
• Targeting ZEB1 or JAK2 represents a potential therapeutic strategy for MS and related autoimmune diseases.