Mechanisms of autoimmune hepatitis.

PURPOSE OF REVIEW: Autoimmune hepatitis (AIH) is a chronic disease characterized by a lymphocyte infiltrate in the liver. For decades, nonspecific immunosuppression has been used to limit chronic liver inflammation. The high risk of relapse, the treatments side effects, and the significant number of refractory patients are the main clinical issues that require efforts to understand AIH immune mechanisms. RECENT FINDINGS: The balance between regulatory CD4 T cells, known to control autoimmunity, and effector CD4 T cells, that recognize liver self-antigens and mediate the liver inflammation, appears central in AIH immune mechanisms. Recent advances in the identification of pathogenic auto-reactive CD4 T cells, and of new mechanisms of immune regulatory defects in AIH patients, give new insights into the pathophysiology of this disease. SUMMARY: In this review, we propose an overview of the central role of CD4 T cells (both regulatory and pathogenic) in mechanisms of AIH, with a focus on recent advances regarding defective regulatory mechanisms and immune profile of auto-reactive CD4 T cells. These findings may have implication for the orientation of new therapeutic strategies to treat AIH, such as regulatory T-cell infusion or targeting B cells and cytokines released by pathogenic CD4 T cells.

Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis.

BACKGROUND & AIMS: In most autoimmune disorders, crosstalk of B cells and CD4 T cells results in the accumulation of autoantibodies. In autoimmune hepatitis (AIH), the presence of anti-soluble liver antigen (SLA) autoantibodies is associated with reduced overall survival, but the associated autoreactive CD4 T cells have not yet been characterised. Herein, we isolated and deeply characterised SLA-specific CD4 T cells in patients with AIH. METHODS: We used brief ex vivo restimulation with overlapping SLA peptides to isolate and phenotype circulating SLA-specific CD4 T cells, and integrative single-cell RNA-seq (scRNA-seq) to characterise their transcriptome and T-cell receptor (TCR) repertoire. Autoreactive TCRs were cloned and used to identify dominant SLA-derived epitopes. SLA-specific CD4 T cells were tracked in peripheral blood through TCR sequencing to identify their phenotypic niche. We further characterised disease-associated peripheral blood T cells by high-content flow cytometry in 42 patients with AIH and 17 controls with non-alcoholic steatohepatitis. RESULTS: Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1+CXCR5-CCR6-CD27+ phenotype. ScRNA-seq revealed their pro-inflammatory/B-helper profile. SLA81-100 and SLA177-204 contain dominant T-cell epitopes. Autoreactive TCR clonotypes were predominantly found in the memory PD-1+CXCR5-CD4 T cells, which were significantly increased in the blood of patients with AIH and supported B-cell differentiation through IL-21. Finally, we identified specific T-cell phenotypes linked to disease activity and IgG level during AIH. CONCLUSIONS: We provide a deep characterisation of rare circulating autoreactive CD4 T cells and identify their peripheral reservoir in AIH. We also propose a specific phenotype of autoreactive T cells related to AIH disease activity, which will be essential to track, delineate, and potentially target these pathogenic cells. LAY SUMMARY: One principal characteristic of autoimmune hepatitis (AIH), like for many other autoimmune diseases, is the accumulation of autoantibodies produced by B lymphocytes following their interaction with autoreactive CD4 T lymphocytes. In this study, we identified and characterised with high resolution these CD4 T cells. This will be essential to track, delineate, and potentially target them during AIH.