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.
|Bry, Lynn; Brigl, Manfred; Brenner, Michael B (2006) CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium. Infect Immun 74:673-81|
|Bry, Lynn; Brenner, Michael B (2004) Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J Immunol 172:433-41|
|Dodge, Ingrid L; Carr, Michelle Woldemar; Cernadas, Manuela et al. (2003) IL-6 production by pulmonary dendritic cells impedes Th1 immune responses. J Immunol 170:4457-64|