Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21
Loss of dendritic cell migration and impaired resistance to Leishmania donovani infection in mice deficient in CCL19 and CCL21
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DOI：
10.4049/jimmunol.176.9.5486
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Kaye, Paul M.
中科院分区：
文献类型：
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作者：
Ato, Manabu;Maroof, Asher;Kaye, Paul M.
APC 和 T 细胞之间的相遇对于启动针对传染性微生物的免疫反应至关重要。在脾脏中，树突状细胞 (DC) 和 T 细胞之间的相互作用发生在动脉周围淋巴鞘 (PALS) 中，DC 和 T 细胞沿着趋化因子梯度从边缘区 (MZ) 迁移到其中。然而，DC从MZ迁移到PALS对于免疫反应和宿主对微生物感染的抵抗力的重要性尚未阐明。在这项研究中，我们报道了小鼠感染杜氏利什曼原虫后，脾DC的迁移受到CCR7配体CCL19/CCL21的调节。与野生型小鼠相比，缺乏这些趋化因子的 plt/plt 突变小鼠中的 DC 活性较低，产生的 IL-12 也较少。当小鼠接受百日咳毒素治疗时，也会发现类似的结果，百日咳毒素会阻断体内趋化因子信号传导。根据脾脏和肝脏寄生虫负荷确定，与野生型小鼠相比，plt/plt 小鼠对杜氏乳杆菌感染的易感性增加。感染后第 14 天的脾细胞因子谱分析表明，野生型和 plt/plt 小鼠中 IFN-γ 和 IL-4 mRNA 的积累相当。相比之下，plt/plt 小鼠中 IL-10 mRNA 的积累升高。此外，plt/plt 小鼠出现延迟的肝肉芽肿反应，并且迁移到肝脏的效应 T 细胞较少。综上所述，我们得出结论，DC 从 MZ 迁移到 PALS 对于 DC 的完全激活和针对杜氏乳杆菌的保护性免疫的最佳诱导是必要的。
The encounter between APC and T cells is crucial for initiating immune responses to infectious microorganisms. In the spleen, interaction between dendritic cells (DC) and T cells occurs in the periarteriolar lymphoid sheath (PALS) into which DC and T cells migrate from the marginal zone (MZ) along chemokine gradients. However, the importance of DC migration from the MZ into the PALS for immune responses and host resistance to microbial infection has not et been elucidated. In this study, we report that following Leishmania donovani infection of mice, the migration of splenic DC is regulated by the CCR7 ligands CCL19/CCL21. DC in plt/plt mutant mice that lack these chemokines are less activated and produce less IL-12, compared with those in wild-type mice. Similar findings are seen when mice are treated with pertussis toxin, which blocks chemokine signaling in vivo. plt/plt mice had increased susceptibility to L. donovani infection compared with wild-type mice, as determined by spleen and liver parasite burden. Analysis of splenic cytokine profiles at day 14 postinfection demonstrated that IFN-gamma and IL-4 mRNA accumulation was comparable in wild-type and plt/plt mice. In contrast, accumulation of mRNA for IL-10 was elevated in plt/plt mice. In addition, plt/plt mice mounted a delayed hepatic granulomatous response and fewer effector T cells migrated into the liver. Taken together, we conclude that DC migration from the MZ to the PALS is necessary for full activation of DC and the optimal induction of protective immunity against L donovani.