title: TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells.
abstract: 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.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Harvard Medical School, Boston, MA 02115, USA.
authors: Norimoto
authors: N
authors: Kobayashi
authors: Piia
authors: P
authors: Karisola
authors: Victor
authors: V
authors: Peña-Cruz
authors: David M
authors: DM
authors: Dorfman
authors: Masahisa
authors: M
authors: Jinushi
authors: Sarah E
authors: SE
authors: Umetsu
authors: Manish J
authors: MJ
authors: Butte
authors: Haruo
authors: H
authors: Nagumo
authors: Irene
authors: I
authors: Chernova
authors: Baogong
authors: B
authors: Zhu
authors: Arlene H
authors: AH
authors: Sharpe
authors: Susumu
authors: S
authors: Ito
authors: Glenn
authors: G
authors: Dranoff
authors: Gerardo G
authors: GG
authors: Kaplan
authors: Jose M
authors: JM
authors: Casasnovas
authors: Dale T
authors: DT
authors: Umetsu
authors: Rosemarie H
authors: RH
authors: Dekruyff
authors: Gordon J
authors: GJ
authors: Freeman
mesh_terms: D000818:Animals; D017209:Apoptosis; D003713:Dendritic Cells / Q000378:metabolism; D000072596:Hepatitis A Virus Cellular Receptor 1; D006801:Humans; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C491143:HAVCR1 protein, human; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010718:Phosphatidylserines; D011991:Receptors, Virus; C500399:TIM-4 protein, mouse; C512411:TIMD4 protein, human