Mapping of class II HLA restriction of SepSecS-specific CD4 T-cell epitopes in autoimmune hepatitis

Year: 2026

Type: article

Abstract: BACKGROUND & AIMS: Autoreactive CD4 T cells, which recognize liver self-antigens such as SepSecS, are potentially main drivers of the chronic inflammatory response during autoimmune hepatitis (AIH). Previous studies have revealed SepSecS epitopes often associated with HLA-DRB1∗03 or HLA-DRB1∗04 restriction, two alleles enriched in AIH population. However, human leukocyte antigen (HLA) restriction of numerous SepSecS epitopes remains incomplete, and whether they could be presented by non-HLA-DR molecules remains unclear. Here, we investigated epitope recognition and HLA restriction of SepSecS-specific CD4 T cells from AIH patients. METHODS: We cloned 17 T-cell receptor αβ (TCRαβ) from the most expanded SepSecS-specific CD4 T cells of five AIH patients from our previous studies into a murine hybridoma T-cell line. The epitope reactivity of each TCR cell line was identified via IL-2 secretion following culture with 20-mer overlapping peptides of the SepSecS protein and immortalized B-cell lines. HLA restriction was defined using HLA blocking antibodies. We analyzed 484 SepSecS-specific TCRs from nine AIH patients using GLIPH2 algorithm. CD154 activation-induced marker assay was used to evaluate the SepSecS epitope reactivity in AIH patients (n = 11). RESULTS: epitope represents 15% to 67% of total SepSecS CD4 T-cell reactivity in HLA-DPA1∗02:01∼HLA-DPB1∗01:01 AIH patients (n = 5). CONCLUSIONS: We highlighted that SepSecS epitopes could be presented by HLA-DR and non-HLA-DR molecules to autoreactive CD4 TCRs with potentially conserved CDR3 motifs for common epitope recognition. IMPACT AND IMPLICATIONS: In AIH, SepSecS is a key autoantigen targeted by the adaptive immune system, but only few T-cell epitopes are defined and associated with a precise HLA restriction. By reconstructing TCRs from the most expanded SepSecS-specific CD4 T cells of AIH patients, we identified new T-cell epitopes and their specific class II HLA restriction, including peptides presented by non-HLA-DR molecules. From a clinical perspective, these findings could be used to develop tools to track the frequency of autoreactive T cells in patients. This work could also pave the way for self-antigen-specific immunotherapies, such as peptide-based desensitization or the development of HLA-multimer technologies to selectively deplete or reprogram pathogenic T cells without inducing systemic immunosuppression.

Source: JHEP Reports

DOI: 10.1016/j.jhepr.2026.101952

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, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Antoine, Centre de Recherche Saint-Antoine, Fondation pour l’innovation en Cadiométabolisme et Nutrition, Hôpital Paul-Brousse, Hôpital Beaujon, Université de Nantes, Benaroya Research Institute

Language: English

Topic: Liver Diseases and Immunity

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,110

Funders: Fondation Maladies Rares, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Labex Immuno-Oncology

OpenAlex ID: W7167270785