Type I Interferon-Regulated T Helper Development

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): 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.