Nakayama Masafumi, Akiba Hisaya, Takeda Kazuyoshi, Kojima Yuko, Hashiguchi Masaaki, Azuma Miyuki, Yagita Hideo, Okumura Ko
Department of Immunology, Biomedical Research Center, Juntendo University School of Medicine, Tokyo, Japan.
Blood. 2009 Apr 16;113(16):3821-30. doi: 10.1182/blood-2008-10-185884. Epub 2009 Feb 17.
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.
巨噬细胞和树突状细胞（DCs）等吞噬细胞吞噬凋亡细胞以维持外周免疫耐受。然而，吞噬细胞识别死亡细胞的机制尚未完全阐明。在此，我们证明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。虽然Tim-4在腹膜驻留巨噬细胞上高度表达，但Tim-3在腹膜渗出巨噬细胞、单核细胞和脾脏DCs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单克隆抗体抑制CD8(+) DCs对凋亡细胞的吞噬作用，导致体外和体内死亡细胞相关抗原的交叉呈递减少。给予抗Tim-3以及抗Tim-4单克隆抗体可诱导自身抗体产生。这些结果表明Tim-3在凋亡细胞吞噬和交叉呈递中起关键作用，这可能与外周耐受有关。
