Gastroenterology

Gastroenterology

Volume 133, Issue 5, November 2007, Pages 1522-1533
Gastroenterology

Basic–Alimentary Tract
TIM-4 Expressed by Mucosal Dendritic Cells Plays a Critical Role in Food Antigen–Specific Th2 Differentiation and Intestinal Allergy

https://doi.org/10.1053/j.gastro.2007.08.006Get rights and content

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.

Section snippets

Mice

Balb/c and C57BL/6 mice (male, 6–8 weeks old) were purchased from the Charles River Laboratory (Wilmington, MA). DO11.10 TCR transgenic mice that recognize an OVA peptide in the context of I-Ad major histocompatibility complex class II (MHC II) molecules were purchased from the Jackson Laboratory (Bar Harbor, ME). The experiments were approved by the Animal Research Ethics Board at McMaster University.

Murine Model of Intestinal Allergy

C57BL/6 mice were sensitized intraperitoneally with SEB (10 μg/mouse), OVA (20 μg/mouse), or

Localization of TIM-4 Expression to DCs in Intestinal Mucosa

Apart from its high expression in the thymus, recent evidence has indicated that TIM-4 also is expressed by DCs located in the spleen and lymph nodes and only weakly is expressed in nonlymphoid tissues such as the lung and liver.13 To begin investigating the role of TIM-4 in the immune regulation of intestinal allergy, we first examined its expression and regulation within the jejunal intestinal mucosa by immunoconfocal microscopy. We found that jejunal mucosa of naive mice had easily

Discussion

Although the development of Th2 cells is believed to be a critical step in the immune mechanisms of food allergy, the factors and mechanisms involved in the initiation of food antigen–specific Th2 activation remain poorly understood. Recent evidence suggests that increased exposure of the mucosal immune system to both bacterial toxins and food antigens predisposes the host to food antigen sensitization and allergy.8, 9 However, little is known about the molecular mechanisms by which microbial

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    Supported by funds from the Canadian Institutes of Health Research (P.–C.Y.).

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