Chronic liver diseases—whether of metabolic, alcoholic, viral, or autoimmune origin—are characterized by persistent inflammation, which constitutes the pathogenic link between parenchymal cell death and the progression of fibrosis toward end-stage cirrhosis. To date, no antifibrogenic therapy is available, underscoring the need for a better understanding of the crosstalk between immune cells, fibrogenic cells, and hepatocytes. While the innate immune response and the role of macrophages have been extensively studied, conventional CD4 T cells also represent a major source of inflammatory mediators. Among them, Th17 cells form a heterogeneous and plastic population capable of producing, in addition to interleukin-17A (IL-17A), interferon-γ (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF); this combination defines a subset with enhanced pathogenic potential, whose involvement in hepatic fibrosis had remained unexplored.
Drawing on both human samples and murine models, the authors establish that autophagy—an essential cellular recycling pathway and a regulator of the inflammatory response of immune cells—is deficient in the CD4 T cells of patients with advanced fibrosis. To test the causal role of this defect, the team generated mice with a deletion of the ATG5 gene specifically in T cells, thereby abolishing autophagy. The chronic liver injury model relied on the administration of carbon tetrachloride (CCl4). Co-culture experiments between CD4 T cells and hepatic myofibroblasts, hepatocytes, or bone marrow–derived macrophages, complemented by transwell systems and neutralizing antibodies, made it possible to dissect the mediators involved.
The loss of autophagy promotes the emergence of pathogenic IL-17A⁺ IFN-γ⁺ Th17 cells that drive hepatic fibrosis in mice. Mechanistically, these autophagy-deprived hepatic CD4 T cells adopt a glycolytic Th17 phenotype associated with increased release of type 3 cytokines (IL-17A and GM-CSF), steering myofibroblasts, hepatocytes, and macrophages toward a pro-inflammatory profile. Conversely, the authors show that autophagy can be restored in the CD4 T cells of patients with extensive hepatic fibrosis, which reduces the frequency of pathogenic Th17 cells and GM-CSF levels. Moreover, limited fibrosis is observed in mice in which the Rubicon gene, a negative regulator of autophagy, is deleted specifically in T cells.
This work identifies CD4 T cell autophagy as a key therapeutic target for controlling inflammation-induced fibrosis in chronic liver injury.