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

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.

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Publication Details

Journal
Nature Communications
Published
2025-01-29
DOI
https://doi.org/10.1038/s41467-025-56363-2
Citations
8
Primary Topic
Liver Diseases and Immunity
Type
article
Field-Weighted Citation Impact
10.58

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article

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

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8 citations
Nature Communications
Liver Diseases and Immunity
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article

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

Fabienne Vavasseur, Florence Tanné, Lucas Brusselle, Amédée Renand, Anaïs Cardon, Caroline Chevalier, Chuang Dong, Jean‐François Mosnier, Pierre Milpied, Christine Silvain, Sophie Conchon, Thomas Guinebretière, Laure Elkrief, Edouard Bardou‐Jacquet, Jérôme Gournay, Matthieu Schnee, Pierre-Jean Gavlovsky, Aurélie Doméné, Jérémie Poschmann, Christoph Schultheiß, Sophie Brouard, Laurine Gil, Ansgar Wilhelm Lohse, Adrien Lannes, Richard Danger, Astrid Imbert, Cynthia Fourgeux, Mascha Binder, Jean‐Paul Judor, Perrine Paul‐Gilloteaux, William W. Kwok, Martin Braud, Marion Khaldi, Sakina Ado, Laura Bernier
article en
8 citations

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.

Nature CommunicationsVol. 16(1)
Centre National de la Recherche Scientifique (FR), Virginia Mason Medical Center (US), Inserm (FR), Universität Hamburg (DE), Aix-Marseille Université (FR), University Hospital of Basel (CH), Centre Hospitalier Universitaire de Nantes (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Centre Hospitalier Universitaire de Tours (FR), Roche (France) (FR), University Medical Center Hamburg-Eppendorf (DE), Centre Hospitalier Universitaire de Poitiers (FR), Institut de Transplantation Urologie en Nephrologie (FR), Centre Hospitalier Universitaire d'Angers (FR), Institut de Recherche en Santé Digestive (FR), Centre d'Investigation Clinique de Nantes (FR), Centre Hospitalier Régional Universitaire de Brest (FR), Centre d’Immunologie de Marseille-Luminy (FR), Centre Hospitalier Départemental Vendée (FR), Centre Hospitalier Universitaire de Rennes (FR), PhysioPathologie des Adaptations Nutritionnelles (FR), Nutrition, métabolismes et cancer (FR), Benaroya Research Institute, Center for Research in Transplantation and Translational Immunology, Université d'Angers (FR), Université de Rennes (FR), Nantes Université (FR)
Aix-Marseille Université, Fondation Maladies Rares, Infrastructures en Biologie Santé et Agronomie, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de Nantes, Conseil Régional des Pays de la Loire
Good health and well-being
Openalex Percentile: Top 1%
Liver Diseases and Immunity
10.58
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