Kikuchi Toshiaki, Kobayashi Takao, Gomi Kazunori, Suzuki Takuji, Tokue Yutaka, Watanabe Akira, Nukiwa Toshihiro
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
J Immunol. 2004 Feb 1;172(3):1727-34. doi: 10.4049/jimmunol.172.3.1727.
Legionella pneumophila is the causative pathogen of Legionnaires' disease, which is characterized by severe pneumonia. In regard to the pathophysiology of Legionella infection, the role of inflammatory phagocytes such as macrophages has been well documented, but the involvement of dendritic cells (DCs) has not been clarified. In this study, we have investigated the immune responses that DCs generate in vitro and in vivo after contact with L. pneumophila. Heat- and formalin-killed L. pneumophila, but not live L. pneumophila, induced immature DCs to undergo similar phenotypic maturation, but the secreted proinflammatory cytokines showed different patterns. The mechanisms of the DC maturation by heat- or formalin-killed L. pneumophila depended, at least in part, on Toll-like receptor 4 signaling or on Legionella LPS, respectively. After transfer to naive mice, DCs pulsed with dead Legionella produced serum Ig isotype responses specific for Legionella, leading to protective immunity against an otherwise lethal respiratory challenge with L. pneumophila. The in vivo immune responses required the Ag presentation of DCs, especially that on MHC class II molecules, and the immunity yielded cross-protection between clinical and environmental strains of L. pneumophila. Although the DC maturation was impaired by live Legionella, macrophages were activated by live as well as dead L. pneumophila, as evidenced by the up-regulation of MHC class II. Finally, DCs, but not macrophages, exhibited a proliferative response to live L. pneumophila that was consistent with their cell cycle progression. These findings provide a better understanding of the role of DCs in adaptive immunity to Legionella infection.
嗜肺军团菌是军团病的致病病原体，其特征为严重肺炎。关于军团菌感染的病理生理学，炎症吞噬细胞如巨噬细胞的作用已有充分记载，但树突状细胞（DCs）的参与情况尚未阐明。在本研究中，我们调查了DCs在体外和体内与嗜肺军团菌接触后产生的免疫反应。热灭活和甲醛灭活的嗜肺军团菌可诱导未成熟DCs发生类似的表型成熟，但分泌的促炎细胞因子表现出不同模式。热灭活或甲醛灭活的嗜肺军团菌诱导DCs成熟的机制至少部分分别依赖于Toll样受体4信号传导或军团菌脂多糖。将用死军团菌脉冲处理的DCs转移到未接触过抗原的小鼠后，可产生针对军团菌的血清Ig同种型反应，从而对嗜肺军团菌的致命性呼吸道攻击产生保护性免疫。体内免疫反应需要DCs的抗原呈递，尤其是MHC II类分子上的抗原呈递，并且这种免疫在嗜肺军团菌的临床菌株和环境菌株之间产生交叉保护。虽然活军团菌会损害DCs的成熟，但巨噬细胞会被活的和死的嗜肺军团菌激活，这可通过MHC II类分子的上调得到证明。最后，DCs而非巨噬细胞对活的嗜肺军团菌表现出增殖反应，这与其细胞周期进程一致。这些发现有助于更好地理解DCs在军团菌感染适应性免疫中的作用。
