Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis.
Adult
Autoantibodies
/ immunology
Autoantigens
/ immunology
B-Lymphocytes
/ immunology
CD4-Positive T-Lymphocytes
/ immunology
Epitopes, T-Lymphocyte
/ analysis
Female
Hepatitis, Autoimmune
/ blood
Humans
Immunologic Memory
Male
Middle Aged
Programmed Cell Death 1 Receptor
/ genetics
Receptors, Antigen, T-Cell
/ genetics
Receptors, CXCR5
/ genetics
Sequence Analysis, RNA
Tumor Necrosis Factor Receptor Superfamily, Member 7
/ genetics
Autoimmune hepatitis
Autoreactive CD4 T cells
Autoreactive TCR clonotypes
Single-cell RNA-seq
Soluble liver antigen
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
20
12
2019
revised:
25
05
2020
accepted:
27
05
2020
pubmed:
11
7
2020
medline:
12
11
2021
entrez:
11
7
2020
Statut:
ppublish
Résumé
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. 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. Autoreactive SLA-specific CD4 T cells were only detected in patients with anti-SLA autoantibodies and had a memory PD-1 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. 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.
Sections du résumé
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
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.
Identifiants
pubmed: 32649971
pii: S0168-8278(20)30453-0
doi: 10.1016/j.jhep.2020.05.053
pii:
doi:
Substances chimiques
Autoantibodies
0
Autoantigens
0
CXCR5 protein, human
0
Epitopes, T-Lymphocyte
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
Receptors, Antigen, T-Cell
0
Receptors, CXCR5
0
Tumor Necrosis Factor Receptor Superfamily, Member 7
0
liver antigen LA-1
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1379-1390Informations de copyright
Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
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.