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

Guinebreteire, T.; Garcia, A.; Dong, C.; Bernier, L.; Huchet, V.; Gavlovsky, P.-J.; Gil, L.; Ado, S.; Chevalier, C.; Judor, J.-P.; Clemenceau, B.; Khaldi, M.; Bardou-Jacquet, E.; Elkrief, L.; Lannes, A.; Silvain, C.; Schnee, M.; Tanne, F.; Lemoinne, S.; De Martin, E.; Vavasseur, F.; Laplaud, D.-A.; Kwok, W. W.; Brouard, S.; Mosnier, J.-F.; Gournay, J.; Milpied, P.; Conchon, S.; Renand, A.

doi:10.1101/2025.08.29.672943

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bioRxiv · 10.1101/2025.08.29.672943

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

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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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Guinebreteire, T., Garcia, A., Dong, C., Bernier, L., Huchet, V., Gavlovsky, P.-J., Gil, L., Ado, S., Chevalier, C., Judor, J.-P., Clemenceau, B., Khaldi, M., Bardou-Jacquet, E., Elkrief, L., Lannes, A., Silvain, C., Schnee, M., Tanne, F., Lemoinne, S., De Martin, E., Vavasseur, F., Laplaud, D.-A., Kwok, W. W., Brouard, S., Mosnier, J.-F., Gournay, J., Milpied, P., Conchon, S., Renand, A.. 2025-09-03. 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. https://doi.org/10.1101/2025.08.29.672943

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