Integrative molecular profiling of autoreactive CD4 T cells in autoimmune hepatitis
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Abstract
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.
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Previous studies in AIDs, including NMOSD, mainly identify T cells with pro-inflammatory or B cell helper function.
“Previous studies in AIDs, including NMOSD, mainly identify T cells with pro-inflammatory or B cell helper function. 16,24-31”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [16]
The Discussion (page not provided) identifies autoreactive CD4 T cells in autoimmune hepatitis with both B-helper function and a pro-inflammatory signature. The Introduction also describes B-helper T cells reported in rheumatoid arthritis and lupus. The paper does not address NMOSD, so it does not support that part of the claim. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThese cells express IL-21 and IFNg but not FOXP3.
“These cells express IL-21 and IFNg but not FOXP3 . 16”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [16]
The Figure 2c passage and Discussion report an IL21 and IFNG gene signature in autoreactive SLA-specific CD4 T cells. Our copy does not state that these cells lack FOXP3; the reported absence is of CXCR5, not FOXP3. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAuto-Th cells with a pro-inflammatory or B cell helper profile are seen in AID patients.
“Auto-Th cells with a pro-inflammatory or B cell helper profile are seen in AID patients, 16,24-31 but comprehensive ex vivo analyses are missing.”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [16]
In vitro expanded AQP4-specific T cells represent Tph-like rather than Tfh-like features.
“Thus, in vitro expanded AQP4-specific T cells represent Tph-like rather than Tfh-like features, as identified in AID patients before. 16,17,54”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [16]
A similar Tph phenotype is present in rheumatoid arthritis and in autoantigen-specific T cells isolated via ARTE from patients with AIH.
“A similar Tph phenotype is present in rheumatoid arthritis 54 and in autoantigen-specific T cells isolated via ARTE from patients with AIH.”
From Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases (2024) · cites this paper as [16]
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- [1]1. Visualization; Writing -original draft; Writing -review & editing);
- [9]9. Sophie Brouard (Funding acquisition; Writing -review & editing); Jérôme Gournay (Conceptualization; Investigation; Methodology; Resources; Supervision; Writing -review & editing); Pierre Milpied (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Visualization; Writing -original draft; Writing -review & editing);
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- Authors
- Renand, A., Cervera-Marzal, I., Gil, L., Dong, C., Garcia, A., Kervagoret, E., Aublé, H., Habes, S., Chevalier, C., Vavasseur, F., Clémenceau, B., Cardon, A., Judor, J.-P., Mosnier, J.-F., Tanné, F., Laplaud, D.-A., Brouard, S., Gournay, J., Milpied, P., & Conchon, S.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Nantes (FR)
- Centre Hospitalier Régional Universitaire de Brest (FR)
- Corresponding author
- Conchon, Sophie
- ORCID
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2020-12
- Volume
- 73
- Issue
- 6
- Pages
- 1379-1390
- ISSN
- 0168-8278 (ISSN-L)
- OpenAlex
- W3041707911
- Cited by
- 80
- References
- 58
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 11 · 2023: 15 · 2022: 16 · 2021: 6 · 2020: 3
- FWCI
- 5.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche
- Topics
- Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Epidemiology › Hepatitis B Virus Studies
- Keywords
- autoimmune hepatitis, autoreactive CD4+ T cells, soluble liver antigen, T cell receptor repertoire, autoantibodies, IL-21, B cell differentiation, T cell phenotype, disease activity, nonalcoholic steatohepatitis, epitope identification
- MeSH terms
- Adult, Autoantibodies, Autoantigens, B-Lymphocytes, Female, Humans, Immunologic Memory, Male, Middle Aged, Receptors, Antigen, T-Cell, CD4-Positive T-Lymphocytes, Sequence Analysis, RNA, Tumor Necrosis Factor Receptor Superfamily, Member 7, Epitopes, T-Lymphocyte, Hepatitis, Autoimmune, Receptors, CXCR5, Programmed Cell Death 1 Receptor
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