TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity

Immunol Rev. 2010 May;235(1):172-89. doi: 10.1111/j.0105-2896.2010.00903.x.


The TIM (T cell/transmembrane, immunoglobulin, and mucin) gene family plays a critical role in regulating immune responses, including allergy, asthma, transplant tolerance, autoimmunity, and the response to viral infections. The unique structure of TIM immunoglobulin variable region domains allows highly specific recognition of phosphatidylserine (PtdSer), exposed on the surface of apoptotic cells. TIM-1, TIM-3, and TIM-4 all recognize PtdSer but differ in expression, suggesting that they have distinct functions in regulating immune responses. TIM-1, an important susceptibility gene for asthma and allergy, is preferentially expressed on T-helper 2 (Th2) cells and functions as a potent costimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells, and generates an inhibitory signal resulting in apoptosis of Th1 and Tc1 cells. TIM-3 is also expressed on some dendritic cells and can mediate phagocytosis of apoptotic cells and cross-presentation of antigen. In contrast, TIM-4 is exclusively expressed on antigen-presenting cells, where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. TIM molecules thus provide a functional repertoire for recognition of apoptotic cells, which determines whether apoptotic cell recognition leads to immune activation or tolerance, depending on the TIM molecule engaged and the cell type on which it is expressed.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adaptive Immunity* / genetics
  • Animals
  • Apoptosis
  • Binding Sites
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Genetic Association Studies
  • Genetic Linkage
  • Hepatitis A Virus Cellular Receptor 1
  • Hepatitis A Virus Cellular Receptor 2
  • Humans
  • Immune System / cytology
  • Immune System / metabolism*
  • Immune Tolerance
  • Immunity, Innate* / genetics
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Phosphatidylserines / metabolism*
  • Protein Conformation
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Receptors, Virus / metabolism
  • Structure-Activity Relationship
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • HAVCR1 protein, human
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 1
  • Hepatitis A Virus Cellular Receptor 2
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphatidylserines
  • Receptors, Cell Surface
  • Receptors, Virus
  • TIMD4 protein, human
  • phosphatidylserine receptor