CD4+ T helper (Th) cells regulate multiple aspects of adaptive cell mediated immunity through the secretion of specific subsets of cytokines. While their activities are critical in responses to pathogenic organisms, CD4+ T cells can also mediate pathologies associated with various inflammatory processes. Specifically, Th2 cells are the key subset of cells that orchestrate the inflammation of asthma through the secretion of the effector cytokines IL-4, IL-5, and IL-13. IL-4 drives Th2 development in CD4+ T cells through the induction of a key transcription factor GATA3. Unlike the innate cytokines IL-12 and IFN-3, we have recently demonstrated that type I interferon (IFN-1/2) inhibits the development and phenotype stability of IL-4-driven Th2 cells. We further demonstrate that IFN-1 blocks this developmental pathway by repressing GATA3 expression. Based on our findings, we propose that IFN-1/2 could block cytokine secretion of asthmatic Th2 cells and reverse the pathogenic effects in vivo. We will address this hypothesis with the following aims:
Aim 1 : Characterize the phenotype and function of Th2 cells undergoing redirection with IFN-1/2.
Aim 2 : Determine the molecular mechanism by which IFN-1/2 blocks GATA3 expression.
Aim 3 : Determine the ability of IFN-1/2 to inhibit phenotype stability and cytokine secretion from Th2 cells isolated from asthmatic patients. The results from these studies will form the basis for new therapeutic approaches to treat asthma involving IFN-1/2.
Asthma is a debilitating inflammatory disease of the lungs that affects millions of people worldwide. While various therapies are in place to provide temporary relief, and in some cases immediate life- saving intervention with inhalers, no treatment has been developed that blocks the chronic progression and maintenance of the disease. Asthma is an immune-mediated disorder caused by the inappropriate activation of CD4+ T cells to normally innocuous molecules in the environment. These activated T cells secrete soluble cytokines, such as interleukin-4, that activate a cascade of inflammatory processes in the lung. Thus, CD4+ T cells represent the primary target for reversing the pathogenesis of asthma. In our studies, we have found that a unique cytokine, type I interferon (IFN- a/b), potently blocks the development of these inflammatory T cells and inhibits their ability to secrete cytokines. Based on this observation, this proposal seeks to understand the mechanism by which IFN-a/b reverses these pathogenic T cells and will determine whether IFN-a/b can block cytokine secretion from these inflammatory T cells isolated from asthma sufferers. These studies will lay the groundwork for more effective and long-lasting treatment for allergy and asthma.
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