INTEGRIN CD103-ROLE IN TH2 PULMONARY IMMUNE RESPONSES

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Asthma, a disease which affects millions worldwide, represents a complex inflammatory disorder characterized by airway inflammation and airway hyperreactivity. Although multiple molecular signals and cells are involved in the pathogenesis of asthma, the CD4+ T lymphocyte has been clearly shown to play a critical role. Specifically, CD4+ T helper cells which are characterized by the secretion of Th2 cytokines. The immunologic pathways by which naive T helper cells differentiate into a Th2 phenotype, however, have yet to be clearly delineated. Integrin alphaE(CD103)beta7 is expressed on lymphocytes, dendritic cells and mast cells, cell types which have been implicated in asthma and the dynamic regulation of mucosal immune responses. The role of integrin alphaEbeta7 in the mediation of pulmonary allergic inflammation and airway reactivity was studied in an in vivo murine model of airway hyperresponsiveness, characterized by high levels of Th2 cytokines, airway hyperresponsiveness and pulmonary inflammation. Integrin alphaE deficient mice were found to have decreased pulmonary inflammation, airway reactivity and markedly reduced levels of Th2 cytokines. In vitro studies demonstrated unfractionated splenocytes from alphaE deficient mice produced significantly lower levels of Th2 cytokines than alphaE+/+ mice. Mixing studies, using purified populations of splenic CD4+ T cells and accessory cells from alphaE deficient and wild type mice, localized the regulation of CD4+ T cell differentiation to a Th2 phenotype to the accessory cell population. Given that alphaEbeta7 is expressed on 25 percent of splenic dendritic cells, the hypothesis that integrin alphaEbeta7 plays a critical role in the regulation of the phenotypic development of CD4+ T cells, mediated by alphaEbeta7 dendritic cells, was developed. To test this hypothesis, in vitro studies will be performed to demonstrate the role of alphaEbeta7+ dendritic cells in the differentiation of CD4+ T cells to a Th2 phenotype and to characterize their phenotypic and functional characteristics. Adoptive transfer experiments will be performed to determine the ability Of alphaEbeta7+ dendritic cells to mediate Th2 polarization in vivo and to confer airway hyperresponsiveness and pulmonary inflammation in response to aerosolized antigen challenge. The mechanisms by which expression of this integrin on dendritic cells mediates the differentiation of nave T helper cells and Th2 pulmonary immune responses will also be examined. These studies may provide significant insights into the role of integrin alphaEbeta7 in T helper cell differentiation and dendritic cell biology.