ZEB2 orchestrates a transcriptional program to safeguard the integrity of human CD4+ Th1 EM cells

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.