title: TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. yangp@mcmaster.ca
authors.forename: Ping-Chang
authors.initials: PC
authors.lastname: Yang
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xing
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: Berin
authors.forename: Johan D
authors.initials: JD
authors.lastname: Soderholm
authors.forename: Bai-Sui
authors.initials: BS
authors.lastname: Feng
authors.forename: Linda
authors.initials: L
authors.lastname: Wu
authors.forename: Calvin
authors.initials: C
authors.lastname: Yeh
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004768:Enterotoxins / Q000494:pharmacology; D005512:Food Hypersensitivity / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D000072596:Hepatitis A Virus Cellular Receptor 1; D007073:Immunoglobulin E / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000494:pharmacology; D018418:Th2 Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D004768:Enterotoxins; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; C500399:TIM-4 protein, mouse; D007073:Immunoglobulin E; C031818:enterotoxin B, staphylococcal; D010047:Ovalbumin