Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung
Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung
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DOI：
10.4049/jimmunol.0903332
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发表时间：
2010-04-15
影响因子：
4.4
通讯作者：
Matsuzaki, Goro
中科院分区：
文献类型：
--
作者：
Yoshida, Yuko Okamoto;Umemura, Masayuki;Matsuzaki, Goro
肉芽肿在肺分枝杆菌的隔离和杀灭中起重要作用；然而，它们的发育和成熟机制尚不清楚。IL-17A参与分枝杆菌感染肺部成熟肉芽肿的形成。因此，IL-17A基因敲除（KO）小鼠在牛分枝杆菌卡介苗（BCG）感染的肺中不能形成成熟的肉芽肿。本研究分析了分枝杆菌感染肺中il - 17a依赖性成熟肉芽肿形成的机制。IL-17A KO小鼠在卡介苗感染后的第14天出现了正常水平的新生肉芽肿，但在第28天没有形成成熟的肉芽肿。这一观察结果表明，IL-17A是肉芽肿从初生阶段到成熟阶段成熟所必需的。表达TCR V γ 4或V γ 6的TCR γ δ T细胞被鉴定为bcg诱导的肺肉芽肿中主要的il - 17a产生细胞。产生IL-17A的TCR γ δ T细胞的过继转移重建了IL-17A KO小鼠肉芽肿的形成。在bcg感染的IL-17A KO小鼠的肺中，ICAM-1和LFA-1的表达降低，并在bcg感染的巨噬细胞与产生IL-17A的TCR γ δ T细胞共培养中诱导其表达。此外，IL-17A KO小鼠不仅表现出成熟肉芽肿形成受损，而且对毒性结核分枝杆菌的保护反应受损。因此，TCR γ δ T细胞产生的IL-17A通过诱导成熟肉芽肿形成在预防结核分枝杆菌感染中起关键作用。中华免疫学杂志，2010,18(4):414- 422。
Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guerin (BCG)-infected lung. This study analyzed the mechanism of IL-17A-dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR gamma delta T cells expressing TCR V gamma 4 or V gamma 6 were identified as the major IL-17A-producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A-producing TCR gamma delta T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A-producing TCR gamma delta T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR gamma delta T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation. The Journal of Immunology, 2010, 184: 4414-4422.