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.
|Estrada, Leonardo D; A?aç, Didem; Farrar, J David (2016) Sympathetic neural signaling via the ?2-adrenergic receptor suppresses T-cell receptor-mediated human and mouse CD8(+) T-cell effector function. Eur J Immunol 46:1948-58|
|Gonzales-van Horn, Sarah R; Estrada, Leonardo D; van Oers, Nicolai S C et al. (2016) STAT4-mediated transcriptional repression of the IL5 gene in human memory Th2 cells. Eur J Immunol 46:1504-10|
|Gonzales-van Horn, Sarah R; Farrar, J David (2015) Interferon at the crossroads of allergy and viral infections. J Leukoc Biol 98:185-94|
|Huber, Jonathan P; Gonzales-van Horn, Sarah R; Roybal, Kole T et al. (2014) IFN-? suppresses GATA3 transcription from a distal exon and promotes H3K27 trimethylation of the CNS-1 enhancer in human Th2 cells. J Immunol 192:5687-94|
|Chowdhury, Fatema Z; Estrada, Leonardo D; Murray, Sean et al. (2014) Pharmacological inhibition of TPL2/MAP3K8 blocks human cytotoxic T lymphocyte effector functions. PLoS One 9:e92187|
|Chowdhury, Fatema Z; Farrar, J David (2013) STAT2: A shape-shifting anti-viral super STAT. JAKSTAT 2:e23633|
|Pyle, David M; Yang, Victoria S; Gruchalla, Rebecca S et al. (2013) IgE cross-linking critically impairs human monocyte function by blocking phagocytosis. J Allergy Clin Immunol 131:491-500.e1-5|
|Chowdhury, Fatema Z; Ramos, Hilario J; Davis, Laurie S et al. (2011) IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo. Blood 118:3890-900|
|Huber, Jonathan P; Farrar, J David (2011) Regulation of effector and memory T-cell functions by type I interferon. Immunology 132:466-74|
|Huber, Jonathan P; Ramos, Hilario J; Gill, Michelle A et al. (2010) Cutting edge: Type I IFN reverses human Th2 commitment and stability by suppressing GATA3. J Immunol 185:813-7|
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