Granzyme A-secreting T cells in allergic inflammation

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 DESCRIPTION (provided by applicant): T helper cells coordinate various types of inflammation by responding to the cytokine environment and differentiating into effector cells that have specialized functions. Many of the specialized functions are conferred by cytokines secreted, but include the expression of additional genes that provide specificity for migration and effector function. To add complexity to the ability of T helper cells to respond to the environment, Th cells can integrate signals from multiple cytokines to generate distinct phenotypes. For example, in the context of allergic inflammation, IL-4 promotes the development of Th2 cells that produce IL-4 and IL-13, although IL-4 in combination with TGFb promotes the development of Th9 cells that predominantly secrete IL- 9. IL-6 is another cytokine detected in many inflammatory diseases, including allergic inflammation that can stimulate acute responses, and promote differentiation of Th cells to the T follicular helper cell phenotype, or, in combination with TGFb, to the IL-17-secreting Th17 subset. In vivo, it is likely that CD4 T cells primed in an allergic environment encounter IL-4, IL-6 and TGFb, and the integration of these signals results in a spectrum of cellular phenotypes that contributes to disease. We have recently identified that CD4 T cells cultured in vitro in the presence of IL-4 and IL-6 develop a unique differentiation profile characterized by a large increase in the proportion of cells that express the serine protease granzyme A (GrA) that has been functionally implicated in autoimmune disease. GrA+ cells lack co-expression of other lineage-specific cytokines, suggesting that these cells may represent a distinct subset of T helper cells. We further show that GrA mRNA is expressed in the skin of mice that are prone to atopic dermatitis and that these same mice have elevated frequencies of peripheral GrA+ CD4 T cells as compared to littermate controls. The goal of this application is to determine if GrA contributes to allergic inflammation, and define the function and derivation of GrA+ CD4 T cells. We hypothesize that GrA-expressing T cells promote allergic inflammation. We will test this hypothesis using approaches in mouse models with T cells that lack or have ectopic expression of GrA to examine the function of these cells in multiple models. We will further define how the Th cell integrates the STAT3 and STAT6 signals required for establishing the GrA-secreting phenotype. These studies will define the function of a novel cell type in allergic disease, and identify potential targets for therapeutic intervention that could reduce symptoms and improve the quality of life of patients suffering from allergic disease.