C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans
C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans
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DOI：
10.1172/jci.insight.124646
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发表时间：
2018-12-20
期刊：
影响因子：
8
通讯作者：
Heegerla, Peter S.
中科院分区：
文献类型：
--
作者：
Verghese, Divya A.;Chun, Nicholas;Heegerla, Peter S.
CD 4（+）滤泡辅助性T（Tfh）细胞是T细胞帮助B细胞的专门提供者，可以作为鼠抗体依赖性慢性移植物抗宿主病（GvHD）的致病介质。使用狼疮样慢性GvHD的亲本-> F1模型，其中Tfh细胞和生发中心（GC）B细胞分化发生超过14天，我们证明了缺乏CD 4（+）T细胞表达的C5 a受体1（C5 ar 1）或药理学C5 aR 1阻断废除了Tfh细胞、GC B细胞和自身抗体的产生/扩增。在以闭塞性细支气管炎综合征（BOS）为表现的慢性GvHD的Tfh细胞依赖性模型中，在已建立疾病的小鼠中启动的C5 aR 1拮抗作用改善了BOS，并消除了Tfh和GC B细胞的相关分化。在RNA测序数据的指导下，使用鼠和人T细胞进行的机制研究表明，C5 aR 1信号转导通过磷酸化磷酸激酶B（AKT）和激活雷帕霉素的哺乳动物靶（mTOR）来放大转录因子c-MAF和细胞因子IL-21的IL-6依赖性表达。除了将C5 aR 1启动的信号传导与Tfh细胞分化联系起来之外，我们的研究结果还表明，C5 aR 1可能是预防和/或治疗Tfh细胞依赖性疾病的有用的治疗靶点，包括具有抗宿主反应性抗体的慢性GvHD患者。
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.