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 Tanné, Fabienne Vavasseur, Lucas Brusselle, Sophie Brouard, William W. Kwok, Jean‐François Mosnier, Ansgar W. Lohse, Jérémie Poschmann, Mascha Binder, Jérôme Gournay, Sophie Conchon, Pierre Milpied, Amédée Renand
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.