Identification of a novel PDC-E2 epitope in primary biliary cholangitis: Application for engineered Treg therapy

• Published in: Journal of autoimmunity 2024-12, Vol.149, p.103327, Article 103327
• Main Authors: Tewari, Ritika, Yang, Soo Jung, McClain, Ethan D., Hu, Alex, Mortensen, Emma, DeSchmidt, Aleah, Chen, Janice, Kancharla, Aravind, Singh, Akhilesh K., James, Eddie A., Burman, Blaire E., Siddique, Asma, Rawlings, David J., Patel, Chandra, Cerosaletti, Karen, Buckner, Jane H.
• Format: Article
• Language: English
• Subjects: Autoantigens - immunology; Dihydrolipoyllysine-Residue Acetyltransferase - immunology; EngTreg; Epitopes, T-Lymphocyte - immunology; Humans; Liver Cirrhosis, Biliary - immunology; Liver Cirrhosis, Biliary - therapy; Novel PDC-E2 epitope; PDC-E2 autoreactive T cells; Primary biliary cholangitis; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2024.103327

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, characterized by progressive destruction of small intrahepatic bile ducts and portal inflammation. Treatment options are limited, with reliance on liver transplantation in advanced cases. The adaptive immune response is implicated in disease pathogenesis by the presence of anti-mitochondrial antibodies targeting the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) in 90–95 % of patients and T cells infiltrating the portal tracts. Here, we examined T cell responses to peptides derived from PDC-E2, with a focus on CD4 T cell responses restricted to HLA Class II DRB4∗01:01, an allele found in 62 % of PBC patients, to uncover PDC-E2 epitopes that could be used for engineered regulatory T cell (Treg; EngTreg) therapy. Using an activation-induced marker assay and single cell RNA-sequencing, we found clonal expansion of CD4 T cells reactive to PDC-E2 epitopes among both T conventional (Tconv) and Tregs. Those T cell receptor (TCR) repertoires were non-overlapping and private and included TCRs specific for a novel PDC-E2 epitope restricted to DRB4∗01:01. CD4 Tconv cells reactive to the PDC-E2 novel epitope showed phenotypic heterogeneity skewed towards T follicular helper cells. Using a TCR specific for this novel PDC-E2 epitope, we created an EngTreg that suppressed PDC-E2-specific polyclonal CD4 Tconv cells from PBC patients. This study advances knowledge of PDC-E2-specific T cell responses and introduces a novel PDC-E2 epitope recognized by both Tconv and Tregs. Generation of EngTreg specific for this epitope provides therapeutic potential for PBC. •Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease.•The pyruvate dehydrogenase complex E2 subunit (PDC-E2) is a major autoantigen in PBC.•Systematic analysis of PDC-E2 identified new epitopes restricted to HLA DRB4∗01:01.•Single cell RNA sequencing identified PDC-E2-specific T cell receptors.•Engineered Tregs specific for PDC-E2 exhibit direct and bystander suppression.