(Applicant?s Abstract) When exposed to antigen, naive T cells differentiate into effector cytokine-producing T cells. Thl cells produce IFN-gamma while Th2 cells produce IL-4, IL-5 and IL-13. Both IL-4 and IFN-gamma have critical roles in the development of asthma. IL-4 strongly potentiates Th2 differentiation in an autocrine loop; Th2 responses are accompanied by high IgE production and recruitment of mast cells and eosinophils, and are strongly associated with allergic asthma and other atopic diseases. IFN-gamma is the major effector cytokine produced by Thl cells. Thl responses are known to be protective for asthma and atopic disease; moreover, a polymorphism in the intronic region of the IFN-gamma gene has been linked to a genetic predisposition to atopic asthma. The long-term interest of my laboratory is to understand the molecular mechanisms underlying cytokine gene expression. In this proposal, we focus on two aspects of this process: the role played by the transcription factor NFAT in regulating IL-4 gene transcription (Aim 1), and regulation of IFN-gamma gene expression at the level of chromatin (Aim 2).
Aim 1. The phenotypes of NFAT-deficient mice suggest that the three NFAT proteins expressed in immune cells differentially regulate IL-4 gene transcription by differentiated Th2 cells. We will investigate the ability of individual NFAT proteins to regulate the early (initiation) and late (termination) phases of IL-4 gene transcription; use chimeric NFAT proteins to map the regions responsible for differential regulation; identify genes selectively induced by NFAT proteins that might be involved in regulating IL-4 gene transcription; and identify nuclear partner proteins that are selectively associated with specific NFAT proteins.
Aim 2. Thl differentiation and activation are accompanied by long-range changes in chromatin structure of the IFN-gamma gene, specifically the appearance and disappearance of intronic DNase I hypersensitive (DH) sites. Moreover T cells lacking NFAT1 show striking impairments in IFN-y gene transcription. We will identify inducible DH sites in the murine and human IFN-gamma genes that might function as distal enhancers; and define the regulatory functions of intronic regions of the IFN-gamma gene, focusing on the constitutive DH sites and on an intronic CA repeat polymorphism which has been linked to asthma by affected sib-pair and multipoint analyses and correlated with levels of IFN-gamma production by PBMC.
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