ZEB2 orchestrates a transcriptional program to safeguard the integrity of human CD4+ Th1 EM cells
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ABSTRACT:
PROVIDER: PRJNA1072732 | ENA |
REPOSITORIES: ENA
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Project description:CD4+ Th1 cells migrate to sites of inflammation, where they are indispensable for eliminating intracellular pathogens. The lineage defining transcription factor T-bet establishes the Th1 transcriptional programme, directing IFNG to drive effector responses and inducing subordinate transcription factors to shape their phenotype. Aberrant Th1 cell activity drives the pathogenesis of multiple autoimmune diseases, but the detailed mechanisms by which Th1 cells maintain or lose their integrity remain largely uncharacterised. Using immunogenomics and high resolution immune phenotyping in human CD4+ cells, we discovered that the transcription factor ZEB2 is lineage restricted to Th1EM cells. Detailed molecular validation using CRISPR/Cas9 deletion of ZEB2, whole genome transcriptomics and pathway mapping has revealed that ZEB2 is a signalling hub for multiple pathways, stabilising the integrity and function of human CD4+ Th1EM cells. Furthermore, our disease linked pathway mapping suggests that ZEB2 is implicated in the control of Th1-mediated autoimmune disease.
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Project description:Age-associated B cells (ABCs) accumulate during infection, aging and autoimmunity, contributing to lupus pathogenesis. Here, we screened for transcription factors driving ABC formation and found Zeb2 was required for human and mouse ABC differentiation in-vitro. ABCs were reduced in ZEB2 haploinsufficient individuals and in mice lacking Zeb2 in B cells. In mice with TLR7-driven lupus, Zeb2 was essential for ABC formation and autoimmune pathology. Zeb2 binds to the +20kb intronic enhancer of Mef2b, repressing Mef2b-mediated germinal center B cell differentiation and promoting ABC formation. Zeb2 also targets genes important for ABC specification and function including Itgax. Zeb2-driven ABC differentiation required Jak-Stat signaling, and treatment with the Jak1/3 inhibitor tofacitinib reduced ABC accumulation in mice and autoimmune patients. Zeb2 thus emerges as a driver of B-cell autoimmunity.
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