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

Saggau C, Bacher P, Esser D, Rasa M, Meise S, Mohr N, Kohlstedt N, Hutloff A, Schacht SS, Dargvainiene J, Martini GR, Stürner KH, Schröder I, Markewitz R, Hartl J, Hastermann M, Duchow A, Schindler P, Becker M, Bautista C, Gottfreund J, Walter J, Polansky JK, Yang M, Naghavian R, Wendorff M, Schuster EM, Dahl A, Petzold A, Reinhardt S, Franke A, Wieczorek M, Henschel L, Berger D, Heine G, Holtsche M, Häußler V, Peters C, Schmidt E, Fillatreau S, Busch DH, Wandinger KP, Schober K, Martin R, Paul F, Leypoldt F, Scheffold A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Immunity Elsevier

Book Volume: 57

Pages Range: 2416-2432

Journal Issue: 10

DOI: 10.1016/j.immuni.2024.08.005

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.

Authors with CRIS profile

Kilian Schober Institute of Microbiology – Clinical Microbiology, Immunology and Hygiene

Involved external institutions

Christian-Albrechts-Universität zu Kiel DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch DE Germany (DE) Universität zu Lübeck DE Germany (DE) Universität des Saarlandes (UdS) DE Germany (DE) Berliner Institut für Gesundheitsforschung (BIH) DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH) Technische Universität Dresden DE Germany (DE) Miltenyi Biotec GmbH DE Germany (DE) Université Sorbonne Paris Cité FR France (FR) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Saggau, C., Bacher, P., Esser, D., Rasa, M., Meise, S., Mohr, N.,... Scheffold, A. (2024). Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases. Immunity, 57(10), 2416-2432. https://doi.org/10.1016/j.immuni.2024.08.005

MLA:

Saggau, Carina, et al. "Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases." Immunity 57.10 (2024): 2416-2432.

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