Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation
Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation
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DOI：
10.1182/blood-2008-10-185884
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发表时间：
2009-04-16
期刊：
影响因子：
20.3
通讯作者：
Okumura, Ko
中科院分区：
文献类型：
--
作者：
Nakayama, Masafumi;Akiba, Hisaya;Okumura, Ko
吞噬细胞如巨噬细胞和树突状细胞（DC）吞噬凋亡细胞以维持外周免疫耐受。然而，吞噬细胞识别垂死细胞的机制尚未完全了解。在这里，我们证明了T细胞免疫球蛋白粘蛋白-3（Tim-3）通过IgV结构域中的FG环识别凋亡细胞，并且对于吞噬细胞清除凋亡细胞至关重要。Tim-4在腹膜驻留巨噬细胞上高度表达，而Tim-3在腹膜渗出物巨噬细胞、单核细胞和脾DC上表达，表明不同吞噬细胞使用不同的Tim介导的吞噬途径。此外，抗Tim-3 mAb可抑制CD 8（+）DC对凋亡细胞的吞噬作用，从而减少体内外死亡细胞相关抗原的交叉呈递。施用抗Tim-3以及抗Tim-4 mAb诱导自身抗体产生。这些结果表明Tim-3在吞噬凋亡细胞和交叉呈递中的关键作用，这可能与外周耐受有关。（血。2009; 113：3821-3830）
Phagocytes such as macrophages and dendritic cells (DCs) engulf apoptotic cells to maintain peripheral immune tolerance. However, the mechanism for the recognition of dying cells by phagocytes is not fully understood. Here, we demonstrate that T-cell immunoglobulin mucin-3 (Tim-3) recognizes apoptotic cells through the FG loop in the IgV domain, and is crucial for clearance of apoptotic cells by phagocytes. Whereas Tim-4 is highly expressed on peritoneal resident macrophages, Tim-3 is expressed on peritoneal exudate macrophages, monocytes, and splenic DCs, indicating distinct Tim-mediated phagocytic pathways used by different phagocytes. Furthermore, phagocytosis of apoptotic cells by CD8(+) DCs is inhibited by anti-Tim-3 mAb, resulting in a reduced cross-presentation of dying cell-associated antigens in vitro and in vivo. Administration of anti-Tim-3 as well as anti-Tim-4 mAb induces autoantibody production. These results indicate a crucial role for Tim-3 in phagocytosis of apoptotic cells and cross-presentation, which may be linked to peripheral tolerance. (Blood. 2009; 113: 3821-3830)