TIM-4 expressed by mucosal dendritic cells plays a critical role in food antigen-specific Th2 differentiation and intestinal allergy.
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.
Yang
Ping-Chang
PC
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. yangp@mcmaster.ca
Xing
Zhou
Z
Berin
Cecilia M
CM
Soderholm
Johan D
JD
Feng
Bai-Sui
BS
Wu
Linda
L
Yeh
Calvin
C
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*
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