Hepatic leukemia factor directs tissue residency of proinflammatory CD4+ T cells

CD4+ tissue-resident memory T cells (TRM) contribute to both host defense and pathogenesis of chronic inflammatory diseases. However, the molecular mechanisms that direct tissue residency and functional heterogeneity of CD4+ TRM remain unknown. We herein show that the transcription factor, hepatic leukemia factor (HLF), directs the tissue residency program and functionality of CD4+ TRM. HLF simultaneously upregulates tissue retention receptors and downregulates tissue egress receptors via changes in chromatin accessibility, and drives proinflammatory CD4+ TRM by inducing Bhlhe40. Genetic deletion of Hlf inhibits CD4+ TRM generation, consequently ameliorating airway tissue inflammation in vivo. In humans, HLF-positive CD4+ TRM from inflamed airway tissue have a tissue residency signature and express inflammatory cytokines. HLF is therefore a central regulator of proinflammatory CD4+ TRM development and function.