Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation
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.
Authors
- Charles Caër (ORCID: https://orcid.org/0000-0002-2735-2423)
- Rémy Nicolle (ORCID: https://orcid.org/0000-0001-8084-1173)
- Hélène Gilgenkrantz (ORCID: https://orcid.org/0000-0001-6770-4561)
- Sukriti Baweja (ORCID: https://orcid.org/0000-0002-8677-9857)
- Sophie Lotersztajn (ORCID: https://orcid.org/0000-0002-0053-7807)
- Adel Hammoutène (ORCID: https://orcid.org/0000-0001-6928-7431)
- Tristan Thibault-Sogorb (ORCID: https://orcid.org/0000-0001-6052-5536)
- Valérie Paradis (ORCID: https://orcid.org/0000-0003-3142-3762)
- Loredana Saveanu (ORCID: https://orcid.org/0000-0003-3138-7968)
- Emmanuel Weiss (ORCID: https://orcid.org/0000-0002-2854-9607)
- JingHong Wan (ORCID: https://orcid.org/0000-0002-9274-2460)
- Janany Kandiah
- Morgane Mabire (ORCID: https://orcid.org/0000-0002-2614-7452)
- Camille Pignolet (ORCID: https://orcid.org/0009-0000-2668-5667)
- Rola Al Sayegh
- Mathilde Cadoux
- Margot Azoulai
- Maxime Gasperment
- Marc-Anthony Chouillard
Institutions
- Inserm (FR)
- Université Paris Cité (FR)
- Hôpital Beaujon (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institute of Liver and Biliary Sciences (IN)
- Centre de Recherche sur l'Inflammation (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-24
- DOI
- https://doi.org/10.1038/s41467-025-59218-y
- Citations
- 8
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 10.83
Funders
- Laboratoire d'Excellence Inflamex
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Institut National Du Cancer
- Direction Générale de l’offre de Soins