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TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells

Immunity. 2007 Dec;27(6):927-40. doi: 10.1016/j.immuni.2007.11.011.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis*
  • Dendritic Cells / metabolism
  • Hepatitis A Virus Cellular Receptor 1
  • Humans
  • Lymphocyte Activation
  • Macrophages / immunology
  • Macrophages / metabolism
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • NIH 3T3 Cells
  • Phagocytosis*
  • Phosphatidylserines / chemistry
  • Phosphatidylserines / metabolism*
  • Receptors, Virus / metabolism*
  • T-Lymphocytes / immunology

Substances

  • HAVCR1 protein, human
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphatidylserines
  • Receptors, Virus
  • TIM-4 protein, mouse
  • TIMD4 protein, human