IFN-Gamma Gene Regulation in T Cells and NK Cells

Vanderbilt University, Nashville TN

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Interferon-gamma, (IFN-gamma) plays a critical role in host defenses against infection by intracellular pathogens, is produced by cells of the innate and adaptive immune system, and is induced by signaling through the T cell receptor or cytokine receptors (IL-12 R, IL-18 R). Over- or inappropriate expression of IFN-gamma is a contributory factor to development of autoimmune diseases, lfng gene expression is primarily regulated at the level of transcription. How lfng gene expression is induced by diverse stimuli and how Ifng can be highly expressed in Th1 cells, but silenced in Th2 cells, in response to identical antigen stimulation are poorly understood biological phenomena. These issues are key to understanding regulation of immune responses and provide a means to develop strategies to "re-polarize" immune responses to, for example, dampen lfng gene expression to treat autoimmune disease or induce lfng gene expression for more efficient vaccine development. Because of these unique properties, the Ifng gene is an ideal model system to study transcriptional regulation. Using three separate approaches, reporter transgenic mice, analysis of long-range historic acetylation (> 100 kb), and analysis of chromosome conformation of the Ifng gene region, we find that long-range genomic interactions play requisite roles in Ifng gene transcription. We propose the following aims. First, we will use a transgenic approach, to define distal regulatory elements required for Ifng gene transcription and silencing during effector T cell differentiation and for responses to TCR and cytokine receptor signaling. Second, we will perform detailed analyses of histone modifications to elucidate the contributions of both differentiation and signaling to establishment of these long-range patterns. Third, we will test the hypothesis that the unique chromosome conformation in the Ifng gene region is a dynamic structure that is a result of both development and differentiation. Fourth, we will integrate the above approaches with genetic approaches to define mechanisms by which autoimmune prone NOD T cells bypass normal restrictions and differentiate into Th1/Tc1 cells by IL-12 independent pathways.