Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases
Pro-inflammatory autoantigen-specific CD4<sup>+</sup> 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<sup>+</sup> T cells to humoral autoimmune responses, with implications for therapeutic targeting.
Authors
- Kilian Schober (ORCID: https://orcid.org/0000-0001-9323-9472)
- Johannes Hartl (ORCID: https://orcid.org/0000-0002-4037-9938)
- Mareike Wendorff (ORCID: https://orcid.org/0000-0001-8185-8516)
- Silja Meise
- Frank Leypoldt (ORCID: https://orcid.org/0000-0002-8972-515X)
- Petra Bächer (ORCID: https://orcid.org/0000-0003-4264-6451)
- Julia K. Polansky (ORCID: https://orcid.org/0000-0003-4727-2540)
- Klaus‐Peter Wandinger (ORCID: https://orcid.org/0000-0002-5483-4276)
- Simon Fillatreau (ORCID: https://orcid.org/0000-0002-7730-9917)
- Maria Hastermann (ORCID: https://orcid.org/0000-0003-0769-0115)
- Ankelien Duchow (ORCID: https://orcid.org/0000-0003-0854-7521)
- Patrick Schindler (ORCID: https://orcid.org/0000-0002-8846-121X)
- Andreas Hutloff (ORCID: https://orcid.org/0000-0002-0572-8151)
- Daniela Esser
- A. Petzold (ORCID: https://orcid.org/0000-0001-9599-8632)
- Carina Saggau
- Andreas Dahl (ORCID: https://orcid.org/0000-0002-2668-8371)
- Alexander Scheffold (ORCID: https://orcid.org/0000-0002-0626-343X)
- Marek Wieczorek (ORCID: https://orcid.org/0000-0002-0862-8076)
- Robert Markewitz (ORCID: https://orcid.org/0000-0003-1676-1085)
- Guido Heine (ORCID: https://orcid.org/0000-0003-1467-9862)
- Roland Martinꝉ (ORCID: https://orcid.org/0000-0002-0982-1329)
- Susanne Reinhardt (ORCID: https://orcid.org/0000-0001-9202-105X)
- Friedemann Paul (ORCID: https://orcid.org/0000-0002-6378-0070)
- Jörn Walter (ORCID: https://orcid.org/0000-0003-0563-7417)
- Gabriela Rios Martini
- Vivien Häußler (ORCID: https://orcid.org/0000-0002-7787-7391)
- Dirk Hans Busch (ORCID: https://orcid.org/0000-0001-8713-093X)
- Sarah-Sophie Schacht (ORCID: https://orcid.org/0000-0003-2512-1741)
- Reza Naghavian (ORCID: https://orcid.org/0000-0002-1328-4095)
- Enno Schmidt (ORCID: https://orcid.org/0000-0002-1206-8913)
- Justina Dargvainiene (ORCID: https://orcid.org/0009-0002-4114-3748)
- Judith Gottfreund (ORCID: https://orcid.org/0000-0002-1395-3703)
- Maike M. Holtsche (ORCID: https://orcid.org/0000-0002-5318-5796)
- André Franke (ORCID: https://orcid.org/0000-0003-1530-5811)
- Mareike Becker (ORCID: https://orcid.org/0000-0003-0269-3552)
- Christian Peters (ORCID: https://orcid.org/0000-0001-5033-6571)
- Klarissa Hanja Stürner (ORCID: https://orcid.org/0000-0003-2199-3315)
- Mingxing Yang
- Daniel Berger (ORCID: https://orcid.org/0000-0002-8029-7670)
- Ev-Marie Schuster
- Lea Henschel
- Nora Kohlstedt
- Ina Schröder
- Mahdi Rasa
- Carolin Bautista
- Nicola Mohr
Institutions
- Miltenyi Biotec (Germany) (DE)
- Universität Hamburg (DE)
- Max Delbrück Center (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- University Hospital Schleswig-Holstein (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Institute of Medical Microbiology and Hygiene (DE)
- Center for Systems Biology Dresden (DE)
- Technical University of Munich (DE)
- Saarland University (DE)
- University of Lübeck (DE)
Publication Details
- Journal
- Immunity
- Published
- 2024-09-02
- DOI
- https://doi.org/10.1016/j.immuni.2024.08.005
- Citations
- 55
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 13.23
Funders
- E-Rare
- European Commission
- Deutsche Forschungsgemeinschaft
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Bundesministerium für Bildung und Forschung
- Universität Zürich
- Federalno Ministarstvo Obrazovanja i Nauke