近日，德国基尔大学Alexander Scheffold及其小组发现，特异性自体抗原的CD4⁺ T细胞获得疲劳表型并在人体抗原特异性自身免疫疾病中持久存在。这一研究成果于2024年9月2日在线发表在国际学术期刊《免疫》上。

研究人员表示，促炎自体抗原特异性CD4⁺ T辅助（auto-Th）细胞是自身免疫疾病（AID）的主要调控者。

研究人员旨在通过结合人类白细胞抗原（HLA）四聚体和基于激活的多维体外分析，来表征这些细胞在具有明确自体抗原的人类AID中的特征。在抗水通道蛋白4抗体阳性的视神经脊髓炎谱系疾病（AQP4-NMOSD）患者中，auto-Th细胞表达CD154，但增殖能力和促炎细胞因子显著减少。

相反，伴随FOXP3（经典调节性T细胞（Treg）转录因子）的疲劳相关共抑制受体被表达。auto-Th细胞在体外对检查点抑制产生反应，并提供强效的B细胞帮助。

具有相同疲劳样（ThEx）表型的细胞在可溶性肝抗原（SLA）抗体自身免疫性肝炎和BP180抗体阳性水疱性类天疱疮（分别为肝脏和皮肤的AID）中被发现。尽管最初描述于癌症和慢性感染中，这些数据指出T细胞疲劳作为适应慢性（自我）刺激的常见机制，并将疲劳的CD4⁺ T细胞与体液性自身免疫反应联系起来，对治疗靶向具有重要意义。

附：英文原文

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

Author: 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 Schrder, Robert Markewitz, Johannes Hartl, Maria Hastermann, Ankelien Duchow, Patrick Schindler, Mareike Becker, Carolin Bautista, Judith Gottfreund, Jrn 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 Huler, Christian Peters, Enno Schmidt, Simon Fillatreau, Dirk H. Busch, Klaus-Peter Wandinger, Kilian Schober, Roland Martin, Friedemann Paul, Frank Leypoldt, Alexander Scheffold

Issue&Volume: 2024-09-02

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.

DOI: 10.1016/j.immuni.2024.08.005

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00404-7