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

Thomas Guinebretière; Alexandra Garcia; Chuang Dong; Laura Bernier; Virginie Huchet; Pierre-Jean Gavlovsky; Laurine Gil; Sakina Ado; Caroline Chevalier; Jean‐Paul Judor; Béatrice Clemenceau; Marion Khaldi; Edouard Bardou‐Jacquet; Laure Elkrief; Adrien Lannes; Christine Silvain; Matthieu Schnee; Florence Tanné; Sara Lemoinne; Eléonora De Martin; Fabienne Vavasseur; David Axel Laplaud; William W. Kwok; Sophie Brouard; Jean‐François Mosnier; Jérôme Gournay; Pierre J. Milpied; Sophie Conchon; Amédée Renand

doi:10.1101/2025.08.29.672943

ImmunologybioRxivAug 29, 2025

Preprint

Clonal analysis of SepSecS-specific CD4 T cells reveals a new HLA-DPA102:01/HLA-DPB101:01-restricted immunodominant epitope in autoimmune hepatitis

Thomas Guinebretière iD, Alexandra Garcia iD, Chuang Dong iD, Laura Bernier, Virginie Huchet, Pierre-Jean Gavlovsky iD, Laurine Gil, Sakina Ado, Caroline Chevalier iD, Jean‐Paul Judor, Béatrice Clemenceau iD, Marion Khaldi, Edouard Bardou‐Jacquet iD, Laure Elkrief iD, Adrien Lannes, Christine Silvain iD, Matthieu Schnee iD, Florence Tanné, Sara Lemoinne iD, Eléonora De Martin iD, Fabienne Vavasseur iD, David Axel Laplaud iD, William W. Kwok iD, Sophie Brouard iD, Jean‐François Mosnier iD, , Amédée Renand iD

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.

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