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 Blood, 16 April 2009, Vol. 113, No. 16, pp. 3821-3830.
Prepublished online as a Blood First Edition Paper on February 17, 2009; DOI 10.1182/blood-2008-10-185884.

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PHAGOCYTES, GRANULOCYTES, AND MYELOPOIESIS

Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation

Masafumi Nakayama1, Hisaya Akiba1, Kazuyoshi Takeda1, Yuko Kojima2, Masaaki Hashiguchi3, Miyuki Azuma3, Hideo Yagita1, and Ko Okumura1

1 Department of Immunology and 2 Division of Biomedical Imaging Research, Biomedical Research Center, Juntendo University School of Medicine, Tokyo; and 3 Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

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.


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