Allergic inflammation and Transcriptional Regulation in Th9 cells

Indiana University Indianapolis, Indianapolis IN

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Abstract

? DESCRIPTION (provided by applicant): T helper subsets regulate inflammatory diseases, including the development of allergic lung inflammation associated with asthma. The development of T helper subsets in controlled by a network of transcription factors that promote the expression of cytokines and other genes associated with the ability of a T helper cell to promote disease. This proposal focuses on the most recently identified subset of T helper cells, Th9 cells that differentiate in response to TGF? and IL-4. Experiments in the proposal will define transcription factors that are important for Th9 cells to promote disease. In the previous funding period we determined a Th9 gene signature and a subset of genes that functionally contribute to the Th9 phenotype. We identified the ETS family member PU.1 as a transcription factor that promotes IL-9 production as it represses Th2 cytokine expression, and that PU.1 expression in T cells is important for the development of allergic inflammation. We defined PU.1 as downstream of the TGF? signal, and demonstrated that IRF4 and BATF are downstream of the IL-4/STAT6 signal. We characterized BATF as a factor important for Th9 development and for allergic inflammation. In the next funding period we will define the function of an ETS family member that might be a lineage-defining factor, and has unique function from PU.1. We will determine how these factors promote IL-9 expression, and also determine how they contribute to the pro-allergic phenotype of Th9 cells. We will further determine the mechanism for the ability of BATF to only promote IL-9 production in Th9 cells, and how BATF contributes to allergic inflammation in T helper cell subsets. Together, the proposed experiments will elucidate a network of transcription factors that regulate IL-9 production and promote a functionally pro-allergic T helper cell subset. Moreover, these studies will define novel contributions of T cells t allergic inflammation and potentially identify new targets for therapeutic intervention.