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

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Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases
Immunity ( IF 25.5 ) Pub Date : 2024-09-02 , DOI: 10.1016/j.immuni.2024.08.005
Carina Saggau ₁ , Petra Bacher ₂ , Daniela Esser ₃ , Mahdi Rasa ₄ , Silja Meise ₁ , Nicola Mohr ₁ , Nora Kohlstedt ₁ , Andreas Hutloff ₂ , Sarah-Sophie Schacht ₁ , Justina Dargvainiene ₃ , Gabriela Rios Martini ₂ , Klarissa H Stürner ₅ , Ina Schröder ₃ , Robert Markewitz ₃ , Johannes Hartl ₆ , Maria Hastermann ₇ , Ankelien Duchow ₇ , Patrick Schindler ₇ , Mareike Becker ₈ , Carolin Bautista ₉ , Judith Gottfreund ₁₀ , Jörn Walter ₁₀ , Julia K Polansky ₁₁ , Mingxing Yang ₁₂ , Reza Naghavian ₁₃ , Mareike Wendorff ₁₄ , Ev-Marie Schuster ₁₅ , Andreas Dahl ₁₆ , Andreas Petzold ₁₆ , Susanne Reinhardt ₁₆ , Andre Franke ₁₇ , Marek Wieczorek ₁₈ , Lea Henschel ₁₈ , Daniel Berger ₁₈ , Guido Heine ₁₉ , Maike Holtsche ₂₀ , Vivien Häußler ₂₁ , Christian Peters ₁ , Enno Schmidt ₂₀ , Simon Fillatreau ₂₂ , Dirk H Busch ₂₃ , Klaus-Peter Wandinger ₃ , Kilian Schober ₂₄ , Roland Martin ₂₅ , Friedemann Paul ₇ , Frank Leypoldt ₅ , Alexander Scheffold ₁

Affiliation

Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein (UKSH), Kiel, Germany.
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein (UKSH), Kiel, Germany; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Kiel, Lübeck, Germany.
Institute of Immunology, Christian-Albrechts-University of Kiel and University Hospital Schleswig-Holstein (UKSH), Kiel, Germany; Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Jena, Germany.
Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Kiel, Lübeck, Germany; Department of Neurology, University Hospital Schleswig-Holstein Kiel, Kiel, Germany.
Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité Universitätsmedizin Berlin, Berlin, Germany.
Institute of Experimental Dermatology, Lübeck, Germany; Department of Pediatric Dermatology, Catholic Children's Hospital Wilhelmstift, Hamburg, Germany.
Department of Dermatology, Allergy and Venerology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Department of Genetics and Epigenetics, Saarland University, Saarbrücken, Germany.
Berlin Institute of Health (BIH) at Charité Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany; German Rheumatism Research Centre, a Leibniz Institute (DRFZ), Charité Platz 1, 10117 Berlin, Germany.
Berlin Institute of Health (BIH) at Charité Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353 Berlin, Germany.
Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, Zurich, Switzerland; Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany; Leibniz Institute for Science and Mathematics Education, Kiel, Germany.
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054 Erlangen, Germany.
DRESDEN-concept Genome Center, Technology Platform at the Center for Molecular and Cellular Bioengineering (CMCB), Technical University of Dresden, Dresden, Germany.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Miltenyi Biotec B.V. & Co. KG, Friedrich-Ebert-Straße 68, 51429 Bergisch Gladbach, Germany.
Department of Dermatology and Allergy, University Hospital Schleswig-Holstein, Kiel, Germany.
Institute of Experimental Dermatology, University of Lübeck, Department of Dermatology, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Clinic and Polyclinic for Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Université Paris Cité, CNRS, INSERM, Institut Necker Enfants Malades-INEM, 75015 Paris, France; Université Paris Cité, Faculté de Médecine, Paris, France; AP-HP, Hôpital Necker-Enfants Malades, Paris, France.
Institute for Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany.
Mikrobiologisches Institut - Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Wasserturmstr. 3/5, 91054 Erlangen, Germany; Medical Immunology Campus Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Schlossplatz 1, 91054 Erlangen, Germany.
Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, Zurich, Switzerland; Cellerys AG, Wagistrasse 21, 8952 Schlieren, Switzerland; Institute of Experimental Immunology, University of Zurich, Wintherturerstrasse 191, 8057 Zurich, Switzerland; Department of Clinical Neuroscience, Karolinska Institute, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.

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.

中文翻译：

自身抗原特异性 CD4+ T 细胞获得耗竭的表型，并在人类抗原特异性自身免疫性疾病中持续存在

促炎性自身抗原特异性 CD4+ 辅助性 T 细胞（自身Th）细胞是自身免疫性疾病（AIDs）的中心协调器。我们旨在通过结合基于人类白细胞抗原（HLA） -四聚体和基于活化的多维离体分析来表征具有明确自身抗原的人类 AIDS 中的这些细胞。在水通道蛋白 4 抗体阳性视神经脊髓炎谱系疾病（AQP4-NMOSD）患者中，自身 Th 细胞表达 CD154，但增殖能力和促炎细胞因子强烈降低。相反，耗竭相关的共抑制受体与经典调节性 T 细胞（Treg）转录因子 FOXP3 一起表达。自身 Th 细胞在体外对检查点抑制做出反应，并提供有效的 B 细胞帮助。在肝脏和皮肤的可溶性肝抗原（SLA） - 抗体 - 自身免疫性肝炎和 BP180 抗体阳性大疱性类天疱疮、艾滋病中分别鉴定出具有相同耗竭样（ThEx）表型的细胞。虽然最初在癌症和慢性感染中描述，但我们的数据表明 T 细胞耗竭是适应 AID 类型慢性（自我）刺激的常见机制，并将耗竭的 CD4+ T 细胞与体液自身免疫反应联系起来，对治疗靶向有影响。

更新日期：2024-09-02

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