The integrin alphaEbeta7 is a cell surface protein that is expressed preferentially on T cells in the mucosal epithelium. While it is appreciated that alphaEbeta7 mediates cell adhesion, and plays a role in the homing of T cells to the respiratory and intestinal epithelium, preliminary studies suggest that signaling via alphaEbeta7 may be critical in the differentiation of CD4 + T cells into TH2 cells. This alteration in T cell cytokine production is biologically significant since in a murine model of ovalbumin induced pulmonary hypersensitivity, mice receiving anti-alphaE mAb or mice genetically deficient in alphaE have decreased cellularity of the bronchoalveolar lavage fluid, lower levels of TH2 cytokines, and less airway hyperresponsiveness. The investigators' hypothesis is that T cell signaling through the alphaEbeta7 integrin is critical in the generation of TH2 responses. In the absence of alphaE , the TH1 response in enhanced as a consequence of a shift in the TH1 / TH2 balance. Since TH1 cytokines are critical to the control and resolution of infections caused by intracellular microbial pathogens, they predicted that blockade or deletion of alphaE may augment the resistance to these infections. Consistent with this novel function of the alphaEbeta7 integrin, their preliminary data indicates that the alphaE deficient mouse is more resistant to the development of tuberculosis. The increased resistance of the alphaE deficient mouse to tuberculosis defines alphaE as a susceptibility gene. This proposal will determine how alphaEbeta7 modifies the susceptibility to Mycobacterium tuberculosis (Erdman) in mice that are inoculated by the respiratory route using an aerosol delivery system.
The specific aims are: 1) Assess the pathogenesis of tuberculosis in alphaE deficient (alphaE-/-) and wild type (alphaE + /+) BALB/c mice; 2) Examine whether the cytokine response to M. tuberculosis is altered in alphaE deficient mice; and 3) Investigate potential mechanisms by which alphaEbeta7 may affect susceptibility to tuberculosis.
