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Spontaneous Development of an Autoimmune Hepatitis – Primary Biliary Cirrhosis Overlap Syndrome in dnTGFβRII Aire-/- mice

ABSTRACT: Autoimmune regulator (Aire) and TGF-β signaling play an important role in central tolerance and peripheral tolerance respectively, by eliminating or suppressing the activity of autoreactive T cells. We have previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cirrhosis (PBC) like disease. We hypothesized that by introducing the AIRE gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrate that while dnTGFβRII Aire-/- mice do manifest key histologic and serologic features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA-seq and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire-/- mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti-CD8α antibody significantly alleviated hepatic inflammation and prolonged the lifespan of these mice. Finally, RNA-seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice develop an autoreactive CD8+ T cell mediated autoimmune cholangitis with concurrent hepatitis that exhibits key histological and serological features of the AIH-PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE223894 | GEO | 2023/02/21

REPOSITORIES: GEO

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Project description:Background & Aims: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies targeting specific self-antigen like the Soluble Liver Antigen (SLA or SepSecs) in autoimmune hepatitis (AIH). But the associated autoreactive CD4 T cells have not been characterized yet. Here we isolated and deeply characterized SLA-specific CD4 T cells in AIH patients. Methods: We used brief ex vivo re-stimulation with overlapping SLA-derived peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterize their transcriptome and T cell receptor (TCR) repertoire. Identified auto-reactive TCRs were reconstituted cloned and expressed in T cell hybridoma to identify dominant SLA-derived CD4 T cell epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing, to identify their phenotypic niche. We further characterized disease-associated peripheral blood T cells by high content flow cytometry in an additional cohort of n=42 AIH patients and n=17 non-alcoholic steatohepatitis (NASH) controls. Results: Frequency of autoreactive SLA-specific CD4 T cells was associated with anti-SLA autoantibodies and had a memory CD45RA-CD27+PD-1+CXCR5-CCR6- phenotype. ScRNA-seq revealed their pro-inflammatory/B-Helper profile (IL21, IFNG, TIGIT, CTLA4, NR3C1, CD109, KLRB1 and CLEC2D). SLA81-100 and SLA177-204 contain dominant T cell epitopes. Autoreactive TCR clonotypes were restricted to the memory PD-1+CXCR5- CD4 T cells which was significantly increased in the blood of AIH patients and supported B cell differentiation through IL-21. Finally, we identified a specific phenotype (CD45RA-PD-1+CD38+CXCR5-CD127-CD27+) of T cells linked to disease activity and IgG response during AIH. Conclusions: This work provides for the first time a deep characterization of rare circulating autoreactive CD4 T cells and the identification of their peripheral reservoir in AIH. We also propose a generic phenotype of pathogenic T cells related to AIH disease activity which will be essential to track, delineate and potentially target those pathogenic cells.

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Spontaneous Development of an Autoimmune Hepatitis – Primary Biliary Cirrhosis Overlap Syndrome in dnTGFβRII Aire-/- mice

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