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<p>Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.</p>

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Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月29日

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  • Anaïs Cardon,
  • Thomas Guinebretière,
  • Chuang Dong,
  • Laurine Gil,
  • Sakina Ado,
  • Pierre-jean Gavlovsky,
  • Martin Braud,
  • Richard Danger,
  • Christoph Schultheiß,
  • Aurélie Doméné,
  • Perrine Paul-Gilloteaux,
  • Caroline Chevalier,
  • Laura Bernier,
  • Jean-Paul Judor,
  • Cynthia Fourgeux,
  • Astrid Imbert,
  • Marion Khaldi,
  • Edouard Bardou-Jacquet,
  • Laure Elkrief,
  • Adrien Lannes,
  • Christine Silvain,
  • Matthieu Schnee,
  • Florence Tanne,
  • Fabienne Vavasseur,
  • Lucas Brusselle,
  • Sophie Brouard,
  • William W. Kwok,
  • Jean-François Mosnier,
  • Ansgar W. Lohse,
  • Jeremie Poschmann,
  • Mascha Binder,
  • Jérôme Gournay,
  • Sophie Conchon,
  • Pierre Milpied,
  • Amédée Renand

摘要

Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.