Department of Medicine, Translational Transplant Research Center, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Division of Blood and Marrow Transplant, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA.
JCI Insight. 2018 Dec 20;3(24):124646. doi: 10.1172/jci.insight.124646.
CD4+ follicular helper T (Tfh) cells are specialized providers of T cell help to B cells and can function as pathogenic mediators of murine antibody-dependent chronic graft-versus-host disease (GvHD). Using a parent→F1 model of lupus-like chronic GvHD, in which Tfh cell and germinal center (GC) B cell differentiation occurs over 14 days, we demonstrate that absence of CD4+ T cell-expressed C5a receptor 1 (C5ar1) or pharmacological C5aR1 blockade abrogated generation/expansion of Tfh cells, GC B cells, and autoantibodies. In a Tfh cell-dependent model of chronic GvHD manifested by bronchiolitis obliterans syndrome (BOS), C5aR1 antagonism initiated in mice with established disease ameliorated BOS and abolished the associated differentiation of Tfh and GC B cells. Guided by RNA-sequencing data, mechanistic studies performed using murine and human T cells showed that C5aR1 signaling amplifies IL-6-dependent expression of the transcription factor c-MAF and the cytokine IL-21 via phosphorylating phosphokinase B (AKT) and activating the mammalian target of rapamycin (mTOR). In addition to linking C5aR1-initiated signaling to Tfh cell differentiation, our findings suggest that C5aR1 may be a useful therapeutic target for prevention and/or treatment of individuals with Tfh cell-dependent diseases, including those chronic GvHD patients who have anti-host reactive antibodies.
CD4+滤泡辅助 T（Tfh）细胞是向 B 细胞提供 T 细胞辅助的专业细胞，可作为鼠类抗体依赖性慢性移植物抗宿主病（GvHD）的致病性介质发挥作用。我们利用狼疮样慢性 GvHD 的亲本→F1 模型（其中 Tfh 细胞和生发中心（GC）B 细胞分化发生在 14 天内），证明了缺失 CD4+T 细胞表达的 C5a 受体 1（C5ar1）或药理学 C5aR1 阻断均可消除 Tfh 细胞、GC B 细胞和自身抗体的产生/扩增。在由闭塞性细支气管炎综合征（BOS）表现的 Tfh 细胞依赖性慢性 GvHD 模型中，在已患有疾病的小鼠中起始 C5aR1 拮抗作用可改善 BOS 并消除相关的 Tfh 和 GC B 细胞分化。基于 RNA 测序数据，使用鼠类和人类 T 细胞进行的机制研究表明，C5aR1 信号通过磷酸化蛋白激酶 B（AKT）和激活雷帕霉素哺乳动物靶标（mTOR）来放大 IL-6 依赖性转录因子 c-MAF 和细胞因子 IL-21 的表达。除了将 C5aR1 起始的信号与 Tfh 细胞分化联系起来，我们的研究结果还表明，C5aR1 可能是预防和/或治疗依赖 Tfh 细胞的疾病（包括具有抗宿主反应性抗体的慢性 GvHD 患者）的有用治疗靶标。
