Center for Immunology and Autoimmune Diseases, Institute of Molecular Medicine, the University of Texas Medical School at Houston, TX, USA.
PLoS One. 2012;7(12):e52666. doi: 10.1371/journal.pone.0052666. Epub 2012 Dec 20.
Activation of complement is one of the earliest immune responses to exogenous threats, resulting in various cleavage products including anaphylatoxin C3a. In addition to its contribution to host defense, C3a has been shown to mediate Th2 responses in animal models of asthma. However, the role of C3a on pulmonary Th17 responses during allergic inflammation remains unclear. Here, we show that mice deficient in C3a receptor (C3aR) exhibited (i) higher percentages of endogenous IL-17-producing CD4(+) T cells in the lungs, (ii) higher amounts of IL-17 in the bronchoalveolar lavage fluid, and (iii) more neutrophils in the lungs than wild-type mice when challenged with intranasal allergens. Moreover, adoptive transfer experiments showed that the frequencies of antigen-specific IL-17-producing CD4(+) T cells were significantly higher in the lungs and bronchial lymph nodes of C3aR-deficient recipients than those of wild-types recipients. Bone-marrow reconstitution study indicated that C3aR-deficiency on hematopoietic cells was required for the increased Th17 responses. Furthermore, C3aR-deficient mice exhibited increased percentages of Foxp3(+) regulatory T cells; however, depletion of these cells minimally affected the induction of antigen-specific Th17 cell population in the lungs. Neutralization of IL-17 significantly reduced the number of neutrophils in bronchoalveolar lavage fluid of C3aR-deficient mice. Our findings demonstrate that C3a signals negatively regulate antigen-specific Th17 responses during allergic lung inflammation and the size of Foxp3(+) regulatory T cell population in the periphery.
补体的激活是对外源威胁的最早免疫反应之一，导致产生各种裂解产物，包括过敏毒素 C3a。除了对宿主防御的贡献外，C3a 已被证明在哮喘动物模型中介导 Th2 反应。然而，C3a 在过敏炎症期间对肺部 Th17 反应的作用尚不清楚。在这里，我们表明缺乏 C3a 受体（C3aR）的小鼠在受到鼻内过敏原攻击时表现出：（i）肺部内源性产生 IL-17 的 CD4+T 细胞比例更高，（ii）支气管肺泡灌洗液中 IL-17 含量更高，（iii）肺部中性粒细胞更多，而野生型小鼠则没有。此外，过继转移实验表明，抗原特异性产生 IL-17 的 CD4+T 细胞在 C3aR 缺陷受体小鼠的肺部和支气管淋巴结中的频率明显高于野生型受体小鼠。骨髓重建研究表明，造血细胞上的 C3aR 缺陷是 Th17 反应增加所必需的。此外，C3aR 缺陷小鼠表现出增加的 Foxp3+调节性 T 细胞比例；然而，这些细胞的耗竭对肺部抗原特异性 Th17 细胞群体的诱导影响最小。IL-17 的中和显著减少了 C3aR 缺陷小鼠支气管肺泡灌洗液中的中性粒细胞数量。我们的研究结果表明，C3a 信号在过敏肺炎症期间负调节抗原特异性 Th17 反应，以及外周 Foxp3+调节性 T 细胞群体的大小。
