Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens
Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens
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DOI：
10.1172/jci31990
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Tanaka, Masato
中科院分区：
文献类型：
--
作者：
Miyake, Yasunobu;Asano, Kenichi;Tanaka, Masato
注射凋亡细胞可诱导对细胞相关抗原的免疫应答受到抑制。在此，我们表明静脉注射表达髓鞘少突胶质细胞糖蛋白（MOG）片段的凋亡细胞可降低MOG特异性T细胞应答，并阻止实验性自身免疫性脑脊髓炎（EAE）的发生。由于注射的凋亡细胞最初在脾脏边缘区（MZ）聚集，我们利用转基因小鼠研究了MZ中的巨噬细胞在免疫抑制中的作用，在这些转基因小鼠中，通过注射白喉毒素（DT）可瞬时清除这些细胞。即使预先注射了表达MOG的凋亡细胞，经DT处理的小鼠仍易患EAE。巨噬细胞的缺失导致MZ中注射的濒死细胞清除延迟。在野生型小鼠中，注射的凋亡细胞被CD8α⁺树突状细胞（DCs）选择性吞噬，而CD8α⁺树突状细胞负责抑制对细胞相关抗原的免疫应答。相反，MZ中巨噬细胞的缺失导致注射的濒死细胞被CD8α⁻CD11b⁺树突状细胞异常吞噬。这些结果表明，MZ中的巨噬细胞不仅调节凋亡细胞的有效清除，还调节CD8α⁺树突状细胞对濒死细胞的选择性吞噬，并且这些独特巨噬细胞的功能失常会损害对细胞相关抗原的免疫应答抑制。
Injection of apoptotic cells can induce suppression of immune responses to cell-associated antigens. Here, we show that intravenous injection of apoptotic cells expressing a fragment of myelin oligodendrocyte glycoprotein (MOG) reduced MOG-specific T cell response and prevented the development of EAE. Since injected apoptotic cells accumulated initially in the splenic marginal zone (MZ), the role of macrophages in the MZ in immune suppression was examined using transgenic mice in which these cells could be transiently deleted by diphtheria toxin (DT) injection. DT-treated mice became susceptible to EAE even though MOG-expressing apoptotic cells were preinjected. Deletion of the macrophages caused delayed clearance of injected dying cells in the MZ. In wild-type mice, injected apoptotic cells were selectively engulfed by CD8 alpha(+) DCs, which are responsible for suppression of immune responses to cell-associated antigens. In contrast, deletion of macrophages in the MZ caused aberrant phagocytosis of injected dying cells by CD8 alpha-CD11b(+) DCs. These results indicate that macrophages in the MZ regulate not only efficient clearance of apoptotic cells but also selective engulfment of dying cells by CD8 alpha(+) DCs and that functional failure of these unique macrophages impairs suppression of immune responses to cell-associated antigens.