TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy

Gastroenterology. 2007 Nov;133(5):1522-33. doi: 10.1053/j.gastro.2007.08.006. Epub 2007 Aug 2.


Background & aims: Food allergy accounts for significant morbidity. The etiology and immune mechanisms of food allergy, however, have remained poorly understood. In this study, we aimed to determine the role of T-cell immunoglobulin-domain and mucin-domain (TIM)-4, a recently identified member of cell surface molecules, in the pathogenesis of intestinal allergy in a murine model.

Methods: We report that TIM-4 as well as costimulatory molecules were up-regulated in intestinal mucosal dendritic cells by in vitro or in vivo exposure to Staphylococcus enterotoxin B (SEB). SEB-conditioned intestinal dendritic cells loaded with a food macromolecule ovalbumin (OVA) induced potent OVA-specific T-helper (Th)2 lymphocyte responses in vitro and such Th2 responses were inhibited completely by TIM-4 blockade.

Results: In vivo exposure to both SEB and OVA resulted in OVA-specific Th2 differentiation and intestinal allergic responses including increased serum immunoglobulin E and Th2 cytokine levels, activation of OVA-specific Th2 cells detected both ex vivo and in situ, and mast cell degranulation. Of importance, in vivo abrogation of TIM-4 or its cognate ligand TIM-1 by using a polyclonal antibody remarkably dampened Th2 differentiation and intestinal allergy.

Conclusions: Our study thus identifies TIM-4 as a novel molecule critically required for the development of intestinal allergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism*
  • Dendritic Cells / pathology
  • Disease Models, Animal
  • Enterotoxins / pharmacology
  • Food Hypersensitivity / metabolism
  • Food Hypersensitivity / pathology
  • Food Hypersensitivity / physiopathology*
  • Hepatitis A Virus Cellular Receptor 1
  • Immunoglobulin E / metabolism
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovalbumin / pharmacology
  • Th2 Cells / drug effects
  • Th2 Cells / pathology*


  • Enterotoxins
  • Havcr1 protein, mouse
  • Hepatitis A Virus Cellular Receptor 1
  • Membrane Proteins
  • TIM-4 protein, mouse
  • Immunoglobulin E
  • enterotoxin B, staphylococcal
  • Ovalbumin