西亚试剂：TIM-1 and TIM-4 Glycoproteins Bind Phosphatidylserine and M

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

Norimoto Kobayashi,1 Piia Karisola,2 Victor Peña-Cruz,1 David M. Dorfman,3 Masahisa Jinushi,1 Sarah E. Umetsu,4 Manish J. Butte,5 Haruo Nagumo,1 Irene Chernova,1 Baogong Zhu,1 Arlene H. Sharpe,5 Susumu Ito,6 Glenn Dranoff,1 Gerardo G. Kaplan,7 Jose M. Casasnovas,8 Dale T. Umetsu,2 Rosemarie H. DeKruyff,2 and Gordon J. Freeman1,

1 Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
2 Division of Immunology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
3 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
4 Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, Harvard Medical School, Boston, MA 02115, USA
5 Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
6 Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA
7 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
8 Centro Nacional de Biotecnologia, CSIC, Campus Universidad Autonoma, 28049 Madrid, Spain

Corresponding author
Gordon J. Freeman
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.

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