Expanding Our Understanding of PDC-E2 T Cell Responses in PBC and Their Application for Eng Treg Therapy

Abstract Text: Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease, characterized by progressive destruction of the small intrahepatic bile ducts and portal inflammation. Treatment options are limited with heavy reliance on orthotopic liver transplant for survival in advanced cases. The adaptive immune response is implicated in disease pathogenesis both by the presence of anti-mitochondrial antibodies targeting the major autoantigen, E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), in 90-95% of patients, and CD4 and CD8 T cells infiltrating the portal tracts in affected individuals. Additionally, genetic associations include a strong link to HLA Class II alleles. 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*0101, an allele found in 62% of PBC patients. Using an Activation Induced Marker assay and single cell RNA sequencing, we found clonal expansion of CD4 T cells reactive to PDC-E2 epitopes in both conventional (Tconv) and regulatory T (Treg) cells. The TCR repertoires were non-overlapping and private and included TCRs specific for a novel PDC-E2 epitope restricted to DRB4*0101. CD4 Tconv cells from healthy and PBC subjects that responded to the PDC-E2 novel epitope showed phenotypic heterogeneity skewed towards the T follicular helper cell subset. Using a TCR specific for this novel PDC-E2 epitope, we created an engineered Treg that suppressed PDC-E2 specific polyclonal CD4 Tconv cells from PBC patients, indicating a potential role for engineered Treg therapy targeting PDC-E2 in PBC.