The a2b1 Integrin: Innate Immunity to Pathogens & Tumors

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DESCRIPTION (provided by applicant): The a2a1 integrin is a collagen/laminin receptor expressed on platelets, endothelial cells, fibroblasts, epithelial cells, and subsets of leukocytes. To define the role of the a2a1 integrin in vivo, we created a genetically engineered mouse in which expression of the a2a1 integrin was completely eliminated. Mice deficient in the a2a1 integrin are viable and fertile and develop relatively normally. Quantitative analysis of mammary gland branching morphogenesis demonstrated that branching complexity is markedly diminished in the a2-deficient animals. Although the a2-deficient mice do not manifest a bleed diathesis, platelets from a2-null mice fail to adhere to type I collagen under either static or shear-stress conditions. The a2a1 integrin-null mouse thus exhibits diverse, sometimes subtle, phenotypes consistent with the widespread pattern of integrin expression. Leukocyte integrins are required for development and activation of the immune system and for leukocyte migration to sites of injury, infection, and tumor formation. The a2a1 integrin has not previously been considered to play a major role in immune function. Our exciting preliminary data clearly demonstrate that the a2a1 integrin is required for innate immunity to infectious organisms and possibly tumors. This proposal will directly address the hypothesis that a2a1 integrin expression is required for innate immune function. The specific aims are (1) To define the role of the a2a1 integrin in the immune response to bacteria using Listeria monocytogenes as a model. (2) To define the mechanisms involved in a2a1 integrin mediated immune response to MCMV infection. (3) To determine whether the a2a1 integrin plays a role in tumor immunoediting. In summary, this proposal will determine the role of the a2a1 integrin expression in the innate immune response to bacteria, viruses, and tumors.