Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting

Anaïs Cardon, Thomas Guinebretière, Chuang Dong, Laurine Gil, Sakina Ado, Pierre-jean Gavlovsky, Martin Braud, Richard Danger, Christoph Schultheiß, Aurélie Doméné, Perrine Paul-Gilloteaux, Caroline Chevalier, Laura Bernier, Jean-Paul Judor, Cynthia Fourgeux, Astrid Imbert, Marion Khaldi, Edouard Bardou-Jacquet, Laure Elkrief, Adrien Lannes, Christine Silvain, Matthieu Schnee, Florence Tanne, Fabienne Vavasseur, Lucas Brusselle, Sophie Brouard, William W. Kwok, Jean-François Mosnier, Ansgar W. Lohse, Jeremie Poschmann, Mascha Binder, Jérôme Gournay, Sophie Conchon (), Pierre Milpied () and Amédée Renand ()
Additional contact information
Anaïs Cardon: UMR 1064
Thomas Guinebretière: UMR 1064
Chuang Dong: CIML
Laurine Gil: CIML
Sakina Ado: CIML
Pierre-jean Gavlovsky: UMR 1064
Martin Braud: UMR 1064
Richard Danger: UMR 1064
Christoph Schultheiß: University Hospital Basel
Aurélie Doméné: SFR Bonamy
Perrine Paul-Gilloteaux: SFR Bonamy
Caroline Chevalier: CHU Nantes
Laura Bernier: UMR 1064
Jean-Paul Judor: UMR 1064
Cynthia Fourgeux: UMR 1064
Astrid Imbert: CHU Nantes
Marion Khaldi: CHU Nantes
Edouard Bardou-Jacquet: Institut NUMECAN
Laure Elkrief: Service Hépato-Gastroentérologie
Adrien Lannes: UPRES EA3859, SFR 4208
Christine Silvain: Service Hépato-Gastroentérologie
Matthieu Schnee: Service Hépato-Gastroentérologie, F- 85000
Florence Tanne: Service Hépato-Gastroentérologie
Fabienne Vavasseur: CHU Nantes
Lucas Brusselle: UMR 1064
Sophie Brouard: UMR 1064
William W. Kwok: Benaroya Research Institute
Jean-François Mosnier: UMR 1064
Ansgar W. Lohse: University Medical Center Hamburg-Eppendorf
Jeremie Poschmann: UMR 1064
Mascha Binder: University Hospital Basel
Jérôme Gournay: UMR 1064
Sophie Conchon: UMR 1064
Pierre Milpied: CIML
Amédée Renand: UMR 1064

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.

Date: 2025
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DOI: 10.1038/s41467-025-56363-2

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