Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting
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.
Article Details
Authors (35)
Anaïs Cardon
Thomas Guinebretière
Chuang Dong
Laurine Gil
Sakina Ado
Pierre-jean Gavlovsky
Martin Braud
Richard Danger
Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology–Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
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
Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, Unité Mixte de Recherche 1064, Institute of Urology–Nephrology Transplantation of the University Hospital of Nantes, Nantes, France
William W. Kwok
Jean-François Mosnier
Ansgar W. Lohse
Jeremie Poschmann
Mascha Binder
Jérôme Gournay
Sophie Conchon
Pierre Milpied
Amédée Renand