自身抗原特异性 CD4 T 细胞获得耗尽的表型，并在人类抗原特异性自身免疫性疾病中持续存在。
Autoantigen-specific CD4+ T cells acquire an exhausted phenotype and persist in human antigen-specific autoimmune diseases.
发表日期：2024 Aug 26
作者：
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 Bautista, Judith 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
来源：
IMMUNITY
摘要：
促炎性自身抗原特异性 CD4 T 辅助细胞 (auto-Th) 细胞是自身免疫性疾病 (AID) 的中心协调者。我们的目的是通过结合基于人类白细胞抗原 (HLA) 四聚体和基于激活的多维离体分析，来表征具有确定自身抗原的人类 AID 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障碍（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，与疲劳相关的共抑制受体与 FOXP3（典型的调节性 T 细胞 (Treg) 转录因子）一起表达。 Auto-Th 细胞在体外对检查点抑制作出反应，并提供有效的 B 细胞帮助。分别在可溶性肝抗原（SLA）抗体自身免疫性肝炎和 BP180 抗体阳性大疱性类天疱疮（肝脏和皮肤艾滋病）中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进行了描述，但我们的数据表明，T 细胞耗竭是适应各种 AID 类型的慢性（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，对治疗靶向具有影响。版权© 2024 作者。由爱思唯尔公司出版。保留所有权利。
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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.