Clonal analysis of SepSecS-specific CD4 T cells reveals a new HLA-DPA1*02:01/HLA-DPB1*01:01-restricted immunodominant epitope in autoimmune hepatitis
Year: 2025
Type: preprint
Abstract: Autoreactive CD4 T cells, recognizing liver-self-antigens such as SepSecS, are main drivers of the chronic inflammatory response during autoimmune hepatitis (AIH). Previous studies have uncovered immunodominant SepSecS epitopes often associated with HLA-DRB1*03 or HLA-DRB1*04 restriction, two alleles enriched in AIH population. However, HLA restriction of numerous SepSecS epitopes remains incomplete and it is still unclear if immunodominant epitopes could be presented by non-HLA-DR molecules. Here, we investigated epitope recognition of SepSecS-specific TCRs isolated from AIH patients, and their HLA restriction by generating TCR hybridoma cell lines. Seventeen TCRs recognized eight SepSecS epitopes with four distinct HLA restrictions, including a novel HLA-DPA1*02:01/DPB1*01:01-restricted SepSecS epitope. TCR clustering analysis using GLIPH2 algorithm suggested that this epitope is recognized by multiple distinct TCRs in HLA-DPA1*02:01∼HLA-DPB1*01:01 patients. Our study provides new insights into liver-self-antigen T cell reactivity during AIH, which could offer potential therapeutic strategies by targeting autoreactive CD4 T cells.
Authors: Thomas Guinebretière, Alexandra Garcia, Chuang Dong, Laura Bernier, Virginie Huchet, Pierre-Jean Gavlovsky, Laurine Gil, Sakina Ado, Caroline Chevalier, Jean-Paul Judor, Béatrice Clémenceau, Marion Khaldi, Edouard Bardou-Jacquet, Laure Elkrief, Adrien Lannes, Christine Silvain, Matthieu Schnee, Florence Tanne, Sara Lemoinne, Eleonora De Martin, Fabienne Vavasseur, David-Axel Laplaud, William W. Kwok, Sophie Brouard, Jean-François Mosnier, Jérôme Gournay, Pierre Milpied, Sophie Conchon, Amédée Renand
Institutions: Inserm, Centre Hospitalier Universitaire de Nantes, Center for Research in Transplantation and Translational Immunology, Nantes Université, Centre National de la Recherche Scientifique, Aix-Marseille Université, Centre d’Immunologie de Marseille-Luminy, Centre d'Investigation Clinique de Nantes, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes Angers, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Centre Hospitalier Universitaire de Rennes, Nutrition, métabolismes et cancer, Université de Rennes, Centre Hospitalier Universitaire de Tours, Centre Hospitalier Universitaire d'Angers, Université d'Angers, Centre Hospitalier Universitaire de Poitiers, Centre Hospitalier Départemental Vendée, Centre Hospitalier Régional Universitaire de Brest, Hôpital Saint-Antoine, Assistance Publique – Hôpitaux de Paris, Hôpital Paul-Brousse, Benaroya Research Institute
Language: English
Topic: Liver Diseases and Immunity
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4413946525