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

Autor: Renand A; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Cervera-Marzal I; Aix Marseille Université, CNRS, Inserm, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France., Gil L; Aix Marseille Université, CNRS, Inserm, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France., Dong C; Aix Marseille Université, CNRS, Inserm, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France., Garcia A; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Kervagoret E; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Aublé H; Centre d'Investigation Clinique gastro-nutrition, CHU Nantes, Nantes, France., Habes S; Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France., Chevalier C; Centre d'Investigation Clinique gastro-nutrition, CHU Nantes, Nantes, France., Vavasseur F; Centre d'Investigation Clinique gastro-nutrition, CHU Nantes, Nantes, France., Clémenceau B; Université de Nantes, CHU Nantes, Inserm, CRCINA, Nantes, France., Cardon A; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Judor JP; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Mosnier JF; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France; Service Anatomie et Cytologie Pathologiques, CHU Nantes, Nantes, France., Tanné F; Service d'hépato gastroentérologie, CHU Cavale Blanche, Brest, France., Laplaud DA; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France; Service de Neurologie et CIC 1413, CHU Nantes, Nantes, France., Brouard S; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France., Gournay J; Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France; Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Nantes, France., Milpied P; Aix Marseille Université, CNRS, Inserm, Centre d'Immunologie de Marseille-Luminy, CIML, Marseille, France., Conchon S; Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France. Electronic address: sophie.conchon@univ-nantes.fr.
Jazyk: angličtina
Zdroj: Journal of hepatology [J Hepatol] 2020 Dec; Vol. 73 (6), pp. 1379-1390. Date of Electronic Publication: 2020 Jul 08.
DOI: 10.1016/j.jhep.2020.05.053
Abstrakt: 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. SLA 81-100 and SLA 177-204 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.
Competing Interests: Conflicts of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details.
(Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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