Submitted October 23, 2008
Accepted February 5, 2009
Tim-3 mediates phagocytosis of apoptotic cells and the cross-presentation
Masafumi Nakayama*, Hisaya Akiba, Kazuyoshi Takeda, Yuko Kojima, Masaaki Hashiguchi, Miyuki Azuma, Hideo Yagita, and Ko Okumura
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Division of Biomedical Imaging Research, Biomedical Research Center, Juntendo University School of Medicine, Tokyo, Japan
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan
* Corresponding author; email: nakayama{at}juntendo.ac.jp.
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. While 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.
