Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells
Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells
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DOI：
10.1073/pnas.0909541107
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发表时间：
2010-01-05
影响因子：
11.1
通讯作者：
den Haan, Joke M. M.
中科院分区：
文献类型：
--
作者：
Backer, Ronald;Schwandt, Timo;den Haan, Joke M. M.
脾是对血液传播的病原体产生免疫反应的淋巴器官。脾边缘区的特殊巨噬细胞对吞噬病原体和细胞碎片具有战略意义，但尚不清楚在激活T细胞反应中发挥作用。在这里，我们证明了脾边缘嗜金属巨噬细胞(MMM)是脾树突状细胞(DC)交叉提呈血源性抗原所必需的。我们的数据表明，靶向MMM的抗原和血媒的腺病毒能够有效地被MMM捕获，并专门转移到脾CD8(+)DC用于交叉呈递和激活细胞毒性T淋巴细胞。在抗体靶向或腺病毒感染后，边缘区巨噬细胞的耗尽可防止CD8(+)树突状细胞激活细胞毒性T淋巴细胞。此外，我们还表明，肿瘤抗原靶向MMM是非常有效的抗肿瘤免疫治疗。我们的研究表明，脾MMM通过捕获和浓缩血源性抗原并转移到交叉呈递的DC，在CD8(+)T细胞免疫的初始步骤中发挥重要作用，可用于设计疫苗接种策略，以诱导抗肿瘤细胞毒性T细胞免疫。
The spleen is the lymphoid organ that induces immune responses toward blood-borne pathogens. Specialized macrophages in the splenic marginal zone are strategically positioned to phagocytose pathogens and cell debris, but are not known to play a role in the activation of T-cell responses. Here we demonstrate that splenic marginal metallophilic macrophages (MMM) are essential for cross-presentation of blood-borne antigens by splenic dendritic cells (DCs). Our data demonstrate that antigens targeted to MMM as well as blood-borne adenoviruses are efficiently captured by MMM and exclusively transferred to splenic CD8(+) DCs for cross-presentation and for the activation of cytotoxic T lymphocytes. Depletion of macrophages in the marginal zone prevents cytotoxic T-lymphocyte activation by CD8(+) DCs after antibody targeting or adenovirus infection. Moreover, we show that tumor antigen targeting to MMM is very effective as antitumor immunotherapy. Our studies point to an important role for splenic MMM in the initial steps of CD8(+) T-cell immunity by capturing and concentrating blood-borne antigens and the transfer to cross-presenting DCs which can be used to design vaccination strategies to induce antitumor cytotoxic T-cell immunity.