ZEB2 orchestrates a transcriptional program to safeguard the integrity of human CD4+ Th1 effector memory 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 T-helper 1 (Th1) transcriptional program, directing IFN-γ to drive effector responses and inducing subordinate transcription factors to shape the Th1 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 uncharacterized. Using immunogenomics and high-resolution immune phenotyping in human CD4+ cells, we discovered that the transcription factor ZEB2 is lineage restricted to Th1 effector memory (EM) cells. Detailed molecular validation using CRISPR/Cas9 deletion of ZEB2, whole genome transcriptomics, and pathway mapping, supported by protein expression and assay for functional changes, revealed that ZEB2 is a signaling hub for multiple pathways, stabilizing the integrity and function of human CD4+ Th1 EM cells. Furthermore, our disease-linked pathway mapping and discovery of reduced ZEB2 in a cohort of pediatric ulcerative colitis patients suggests that ZEB2 is implicated in the control of Th1-mediated autoimmune disease.