Department of Pathology, Tufts University School of Medicine, Boston, MA 02111, USA.
J Immunol. 2011 Nov 15;187(10):5328-35. doi: 10.4049/jimmunol.1101445. Epub 2011 Oct 14.
CBA/J mice infected with the helminth Schistosoma mansoni develop severe CD4 T cell-mediated hepatic granulomatous inflammation against parasite eggs associated with a robust Th17 cell response. We investigated the requisites for Th17 cell development using novel CD4 T cells expressing a transgenic TCR specific for the major Sm-p40 egg Ag, which produce IL-17 when stimulated with live schistosome eggs. Neutralization of IL-23 or blockade of the IL-1 receptor, but not IL-6 neutralization, abrogated egg-induced IL-17 secretion by transgenic T cells, whereas exogenous IL-23 or IL-1β reconstituted their ability to produce IL-17 when stimulated by syngeneic IL-12p40-deficient dendritic cells. Kinetic analysis demonstrated that IL-17 production was initiated by IL-23 and amplified by IL-1β. Significantly, schistosome-infected IL-12p40-deficient or IL-1R antagonist-treated CBA/J mice developed markedly reduced hepatic immunopathology with a dampened egg Ag-specific IL-17 response. These results demonstrate that the IL-23-IL-1-IL-17 axis has a central role in the development of severe schistosome egg-induced immunopathology.
CBA/J 小鼠感染曼氏血吸虫后，针对寄生虫卵发生严重的 CD4 T 细胞介导的肝肉芽肿炎症，伴有强烈的 Th17 细胞反应。我们使用表达针对主要 Sm-p40 卵 Ag 的转基因 TCR 的新型 CD4 T 细胞研究了 Th17 细胞发育的必要条件，当用活血吸虫卵刺激时，这些细胞会产生 IL-17。中和 IL-23 或阻断 IL-1 受体，但不中和 IL-6，可消除转基因 T 细胞对卵诱导的 IL-17 分泌，而外源性 IL-23 或 IL-1β 可在刺激同种异体 IL-12p40 缺陷树突状细胞时恢复其产生 IL-17 的能力。动力学分析表明，IL-17 的产生是由 IL-23 启动的，并由 IL-1β 放大。重要的是，感染曼氏血吸虫的 IL-12p40 缺陷型或 IL-1R 拮抗剂处理的 CBA/J 小鼠发生了明显减轻的肝免疫病理学，伴有减弱的卵 Ag 特异性 IL-17 反应。这些结果表明，IL-23-IL-1-IL-17 轴在严重的血吸虫卵诱导免疫病理学的发展中具有核心作用。
