Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation

作者：Rola Al Sayegh, JingHong Wan, Charles Caër, Margot Azoulai, Maxime Gasperment, Sukriti Baweja, Marc-Anthony Chouillard, Janany Kandiah, Mathilde Cadoux, Morgane Mabire, Camille Pignolet, Tristan Thibault-Sogorb, Adel Hammoutène, Valérie Paradis, Loredana Saveanu, Rémy Nicolle, Hélène Gilgenkrantz, Emmanuel Weiss, Sophie Lotersztajn · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-59218-y · 被引用次数：13 · 研究领域：Autophagy in Disease and Therapy、Phagocytosis and Immune Regulation、Endoplasmic Reticulum Stress and Disease

Conventional CD4 T cells represent a major source of inflammatory mediators that drive progression of chronic liver disease to fibrosis and to end-stage cirrhosis. Identification of T cell pathways that limits the inflammatory response could thus have therapeutic relevance. Here we show, using both human samples and mouse models, that autophagy is deficient in CD4 T cells from patients with advanced fibrosis, and that loss of autophagy following genomic deletion of ATG5 in T cells is associated with the emergence of pathogenic IL-17A + IFN-γ + Th17 T cells that drive liver fibrosis in mice. Mechanistically, liver CD4 T cells lacking autophagy display a Th17 glycolytic phenotype associated with enhanced type 3 cytokine (i.e., IL-17A and GM-CSF) release, shifting hepatic myofibroblasts, hepatocytes and macrophages toward a proinflammatory phenotype. We also show that autophagy can be rescued in CD4 T cells from patients with extensive liver fibrosis, leading to decreased frequency of pathogenic Th17 cells and reduced GM-CSF levels; in addition, limited fibrosis is observed in mice in which Rubicon, a negative regulator of autophagy, is deleted specifically in their T cells. Our findings thus implicate autophagy in CD4 T cells as a key therapeutic target to control inflammation-driven fibrosis during chronic liver injury. Liver fibrosis is a consequence of the sustained inflammatory processes underpinning chronic liver disease. Here authors show that autophagy in CD4 T cells is ...