General autoimmunity

Oral

Single-cell analysis of autoreactive CD4 T cells reveals an atypical B helper signature in autoimmune hepatitis

Presenting Author(s)

• AR

  Amedee Renand, PhD

  CRTI UMR1064, INSERM, Université de Nantes, Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France

Co-Author(s)

• IC

  Iñaki Cervera-Marzal

  Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
• HA

  Hélène Auble, Pharm.D

  Centre d'Investigation Clinique gastro-nutrition, CHU Nantes, Nantes, France
• LG

  Laurine Gil

  Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
• EK

  Erwan Kervagoret

  CRTI UMR1064, INSERM, Université de Nantes, Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France
• SH

  Sarah Habes, M.D

  Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
• JM

  Jean-François Mosnier, M.D

  Service Anatomie et Cytologie Pathologiques, CHU Nantes, Nantes, France
• SB

  Sophie Brouard, DVM, PhD

  Centre de Recherche en Transplantation et Immunologie (CRTI) UMR 1064, INSERM, Université de Nantes, ITUN, CHU de Nantes
• JG

  Jérôme Gournay, M.D

  Service Hepato-gastro-entérologie et Assistance Nutritionnelle, CHU Nantes, Nantes, France
• PM

  Pierre Milpied, PhD

  Aix Marseille University, CNRS, INSERM, CIML, Marseille, France
• SC

  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 CXCR5^neg PD-1^high CCR6^neg 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 CXCR5^neg PD-1^high CD4 T cell population, which was significantly increased in the blood of AIH patients and shared B helper capacity with the classical CXCR5^high PD-1^high CD4 T_FH 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.