TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and Mediate Uptake of Apoptotic Cells

The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other...

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Bibliographic Details
Published in:	Immunity (Cambridge, Mass.) Mass.), 2007-12, Vol.27 (6), p.927-940
Main Authors:	Kobayashi, Norimoto, Karisola, Piia, Peña-Cruz, Victor, Dorfman, David M., Jinushi, Masahisa, Umetsu, Sarah E., Butte, Manish J., Nagumo, Haruo, Chernova, Irene, Zhu, Baogong, Sharpe, Arlene H., Ito, Susumu, Dranoff, Glenn, Kaplan, Gerardo G., Casasnovas, Jose M., Umetsu, Dale T., DeKruyff, Rosemarie H., Freeman, Gordon J.
Format:	Article
Language:	eng
Subjects:	Animals Apoptosis Binding sites CELLIMMUNO Crystal structure Dendritic Cells - metabolism Hepatitis A Virus Cellular Receptor 1 Humans Kinases Lymphocyte Activation Macrophages - immunology Macrophages - metabolism Membrane Glycoproteins - metabolism Membrane Proteins - chemistry Membrane Proteins - metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL MOLIMMUNO NIH 3T3 Cells Phagocytosis Phosphatidylserines - chemistry Phosphatidylserines - metabolism Receptors, Virus - metabolism Rodents T-Lymphocytes - immunology
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Summary:	The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Here we showed that TIM-4 is expressed on human and mouse macrophages and dendritic cells, and both TIM-4 and TIM-1 specifically bound phosphatidylserine (PS) on the surface of apoptotic cells but not any other phospholipid tested. TIM-4 + peritoneal macrophages, TIM-1 + kidney cells, and TIM-4- or TIM-1-transfected cells efficiently phagocytosed apoptotic cells, and phagocytosis could be blocked by TIM-4 or TIM-1 monoclonal antibodies. Mutations in the unique cavity of TIM-4 eliminated PS binding and phagocytosis. TIM-4 mAbs that blocked PS binding and phagocytosis mapped to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors whose recognition of PS is critical for the efficient clearance of apoptotic cells and prevention of autoimmunity.
ISSN:	1074-7613 1097-4180