Macrophages transfer antigens to dendritic cells by releasing exosomes containing dead-cell-associated antigens partially through a ceramide-dependent pathway to enhance CD4+ T-cell responses
Macrophages transfer antigens to dendritic cells by releasing exosomes containing dead-cell-associated antigens partially through a ceramide-dependent pathway to enhance CD4+ T-cell responses
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巨噬细胞通过释放含有死细胞相关抗原的外泌体，部分通过神经酰胺依赖性途径将抗原转移至树突状细胞，以增强 CD4 T 细胞反应
DOI：
10.1111/imm.12630
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发表时间：
2016-10-01
期刊：
影响因子：
6.4
通讯作者：
Tang, Hua
中科院分区：
文献类型：
--
作者：
Xu, Yingping;Liu, Yi;Tang, Hua
凋亡细胞的快速清除缺陷导致死细胞（晚期凋亡或继发性坏死细胞）的积累，这导致异常免疫应答。然而，很少有人知道是否以及如何巨噬细胞（M φ s）与树突状细胞（DC）的死亡细胞相关抗原在这个过程中的介绍。通过转移大量的死细胞来模拟体内凋亡细胞清除的失败，我们发现M φ s和中性粒细胞是脾脏中吸收死细胞的主要吞噬细胞。此外，M phi s和DC都是由死细胞相关抗原触发的最佳CD4（+）T细胞应答所必需的。重要的是，尽管单独的M phi具有较差的抗原呈递能力，但它们可以将吞噬的抗原转移到DC以进行有效的抗原呈递，从而增强T细胞应答。最后，我们发现，从M phi s释放的外泌体作为一个发射器，以神经酰胺依赖性的方式将抗原部分传递给DC，因为中性鞘磷脂酶抑制剂GW 4869和螺环氧化物的治疗导致T细胞增殖在体外和体内的显着减少。这些发现指出了M phi s和DC之间的一种新的串扰途径，这将有助于解释以凋亡率增加为特征的自身免疫性疾病的可能机制。
Defects in rapid clearance of apoptotic cells lead to an accumulation of dead cells (late apoptotic or secondary necrotic cells), which results in an aberrant immune response. However, little is known about whether and how macrophages (M phi s) cooperate with dendritic cells (DCs) in the presentation of dead-cell-associated antigens in this process. By transferring high numbers of dead cells to mimic a failure of apoptotic cell clearance in vivo, we found that M phi s and neutrophils were the predominant phagocytes in the uptake of dead cells in the spleen. Moreover, both M phi s and DCs were required for an optimal CD4(+) T-cell response triggered by dead-cell-associated antigens. Importantly, although M phi s alone had a poor capacity for antigen presentation, they could transfer phagocytosed antigens to DCs for potent antigen presentation to enhance T-cell responses. Finally, we found that exosomes released from M phi s acted as a transmitter to convey antigens to DCs partially in a ceramide-dependent manner, since treatment with the neutral sphingomyelinase inhibitor GW4869 and spiroepoxide resulted in a significant reduction of T-cell proliferation in vitro and in vivo. These findings point to a novel pathway of cross-talk between M phi s and DCs, which will be helpful to explain possible mechanisms for autoimmune diseases characterized by increased rates of apoptosis.