Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases

Carina Saggau, Petra Bacher, Daniela Esser, Mahdi Rasa, Silja Meise, Nicola Mohr, Nora Kohlstedt, Andreas Hutloff, Sarah Sophie Schacht, Justina Dargvainiene, Gabriela Rios Martini, Klarissa H. Stürner, Ina Schröder, Robert Markewitz, Johannes Hartl, Maria Hastermann, Ankelien Duchow, Patrick Schindler, Mareike Becker, Carolin BautistaJudith Gottfreund, Jörn Walter, Julia K. Polansky, Mingxing Yang, Reza Naghavian, Mareike Wendorff, Ev Marie Schuster, Andreas Dahl, Andreas Petzold, Susanne Reinhardt, Andre Franke, Marek Wieczorek, Lea Henschel, Daniel Berger, Guido Heine, Maike Holtsche, Vivien Häußler, Christian Peters, Enno Schmidt, Simon Fillatreau, Dirk H. Busch, Klaus Peter Wandinger, Kilian Schober, Roland Martin, Friedemann Paul, Frank Leypoldt, Alexander Scheffold

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Pro-inflammatory autoantigen-specific CD4+ T helper (auto-Th) cells are central orchestrators of autoimmune diseases (AIDs). We aimed to characterize these cells in human AIDs with defined autoantigens by combining human leukocyte antigen (HLA)-tetramer-based and activation-based multidimensional ex vivo analyses. In aquaporin4-antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) patients, auto-Th cells expressed CD154, but proliferative capacity and pro-inflammatory cytokines were strongly reduced. Instead, exhaustion-associated co-inhibitory receptors were expressed together with FOXP3, the canonical regulatory T cell (Treg) transcription factor. Auto-Th cells responded in vitro to checkpoint inhibition and provided potent B cell help. Cells with the same exhaustion-like (ThEx) phenotype were identified in soluble liver antigen (SLA)-antibody-autoimmune hepatitis and BP180-antibody-positive bullous pemphigoid, AIDs of the liver and skin, respectively. While originally described in cancer and chronic infection, our data point to T cell exhaustion as a common mechanism of adaptation to chronic (self-)stimulation across AID types and link exhausted CD4+ T cells to humoral autoimmune responses, with implications for therapeutic targeting.

Original languageEnglish
Pages (from-to)2416-2432.e8
JournalImmunity
Volume57
Issue number10
DOIs
StatePublished - 8 Oct 2024

Keywords

  • CD154
  • CD4 T cell exhaustion
  • Foxp3
  • MOGAD
  • antigen-reactive T cell enrichment, ARTE
  • autoantigen-specific T cells
  • autoimmune disease
  • autoimmune hepatitis
  • bullous pemphigoid
  • neuromyelitis optica

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