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General autoimmunity
Oral
Amedee Renand, PhD
CRTI UMR1064, INSERM, Université de Nantes, Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France
Iñaki Cervera-Marzal
Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
Hélène Auble, Pharm.D
Centre d'Investigation Clinique gastro-nutrition, CHU Nantes, Nantes, France
Laurine Gil
Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
Erwan Kervagoret
CRTI UMR1064, INSERM, Université de Nantes, Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France
Sarah Habes, M.D
Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
Jean-François Mosnier, M.D
Service Anatomie et Cytologie Pathologiques, CHU Nantes, Nantes, France
Sophie Brouard, DVM, PhD
Centre de Recherche en Transplantation et Immunologie (CRTI) UMR 1064, INSERM, Université de Nantes, ITUN, CHU de Nantes
Jérôme Gournay, M.D
Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
Pierre Milpied, PhD
Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
Sophie Conchon
Researcher PhD
CRTI UMR1064, INSERM, Université de Nantes, Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France
In autoimmune disorders, CD4 T cell-dependent chronic B cell activation towards multiple self-antigens promotes the production of pathogenic autoantibodies. However, the molecular signature and precise phenotype of autoreactive CD4 T cells in human autoimmunity have been elusive, even more so for rare diseases like autoimmune hepatitis (AIH). Here, we combined brief ex vivo restimulation with pools of overlapping antigen-derived peptides and integrative single-cell RNAseq (scRNAseq) to characterize the circulating CD4 T cell response against Soluble Liver Antigen (SLA or SepSecs) in seropositive (defined as positive for anti-SLA auto-antibodies) and seronegative AIH patients. Only seropositive AIH patients had detectable amounts of SLA-specific CD4 T cells, which had a conserved memory CXCR5neg PD-1high CCR6neg phenotype, and an atypical B helper molecular profile with high expression of IL21, IFNG, TIGIT and CTLA4 among other genes. Strikingly, the expanded SLA-specific CD4 TCR clonotypes identified by scRNAseq were only found in the circulating CXCR5neg PD-1high CD4 T cell population, which was significantly increased in the blood of AIH patients and shared B helper capacity with the classical CXCR5high PD-1high CD4 TFH population. Altogether, our results provide for the first time a fine and comprehensive characterization of autoreactive CD4 T cells in the rare autoimmune disorder AIH, thereby identifying the phenotypic niche and specific molecular signature of pathogenic B helper self-reactive CD4 T cells.