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

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 Hammoutene, Valérie Paradis, Loredana Saveanu, Rémy Nicolle, Hélène Gilgenkrantz, Emmanuel Weiss and Sophie Lotersztajn ()
Additional contact information
Rola Al Sayegh: Centre de Recherche sur l’Inflammation (CRI)
Jinghong Wan: Centre de Recherche sur l’Inflammation (CRI)
Charles Caër: Centre de Recherche sur l’Inflammation (CRI)
Margot Azoulai: Centre de Recherche sur l’Inflammation (CRI)
Maxime Gasperment: Centre de Recherche sur l’Inflammation (CRI)
Sukriti Baweja: Centre de Recherche sur l’Inflammation (CRI)
Marc-Anthony Chouillard: Centre de Recherche sur l’Inflammation (CRI)
Janany Kandiah: Centre de Recherche sur l’Inflammation (CRI)
Mathilde Cadoux: Centre de Recherche sur l’Inflammation (CRI)
Morgane Mabire: Centre de Recherche sur l’Inflammation (CRI)
Camille Pignolet: Centre de Recherche sur l’Inflammation (CRI)
Tristan Thibault-Sogorb: Centre de Recherche sur l’Inflammation (CRI)
Adel Hammoutene: Centre de Recherche sur l’Inflammation (CRI)
Valérie Paradis: Centre de Recherche sur l’Inflammation (CRI)
Loredana Saveanu: Centre de Recherche sur l’Inflammation (CRI)
Rémy Nicolle: Centre de Recherche sur l’Inflammation (CRI)
Hélène Gilgenkrantz: Centre de Recherche sur l’Inflammation (CRI)
Emmanuel Weiss: Centre de Recherche sur l’Inflammation (CRI)
Sophie Lotersztajn: Centre de Recherche sur l’Inflammation (CRI)

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59218-y

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