The integrin alpha-E beta-7 is expressed on leukocytes including T cells, mast cells and dendritic cells (DC). We characterized its expression on T cells and showed that it mediates adhesion to an epithelial adhesion molecule, E-cadherin. We generated alpha-E deficient mice that had reduced numbers of intraepithelial T cells, confirming the in vivo relevance of the interaction. To further reveal the role of alpha-E beta-7 in vivo, we challenged mice with aerosolized OVA in a system that produces an asthma-like Th2 response characterized by high levels of IL-4, IL-5, IL-10 and IL-13 in the airways and associated pulmonary inflammation and airway hyperresponsiveness (AHR). Remarkably, this response was abrogated by anti-alpha-E beta-7, specific mAb. Moreover, OVA aerosolized alpha-E-/- mice failed to develop detectable levels of Th2 cytokines in the airways and had markedly reduced manifestations of pulmonary inflammation and AHR compared to alpha-E+/+ mice. In vitro studies revealed that splenocytes from alpha-E-/- mice produced lower levels of Th2 cytokines and higher levels of Th1 cytokines than splenocytes from alpha-E+/+ mice. This defect in ability to generate a Th2 cytokine response was determined by the genotype of the dendritic cells, not the T cells. Since alpha-E beta-7 is expressed on 25% of DC, we hypothesize that alpha-E beta-7+ DC play an important role in T helper cell differentiation, and that in alpha-E-/- mice, altered localization or function of DC accounts for the inability to develop a strong Th2 response. Here, we propose to characterize the alpha-E beta- 7+ DC, demonstrate their role in generating Th2 polarized responses in vitro and by adoptive transfer in vivo. We will examine the role of the alpha-E beta-7 molecule itself on DC by measuring DC trafficking, signaling, and adhesion to T cells. These experiments are likely to provide new insights into the function of the alpha-E beta-7 integrin, its role in dendritic cell biology and T helper cell differentiation, and have important implications for allergy, asthma and mucosal immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI038578-10
Application #
6857073
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Rothermel, Annette L
Project Start
1995-06-01
Project End
2006-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
10
Fiscal Year
2005
Total Cost
$313,496
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115