IL-4 is a pleiotropic cytokine which drives Th2 differentiation and is produced by a number of cells including mast cells, basophils and Th2 cells. Development of therapeutic intervention for various immunopathologies requires an understanding of the factors controlling IL-4 expression. Due to the numerous and profound effects of IL-4 in immune responses, its expression is tightly regulated. One of several mechanisms regulating IL-4 gene (II4) expression occurs at the level of chromatin. Differences in chromatin accessibility at defined loci results in variability in gene expression """"""""potential"""""""", which confers the relative expression levels upon cellular activation. Recently, our laboratory demonstrated that Ikaros, a zinc-finger DMA binding transcription factor associated with chromatin remodeling, regulates II4 locus accessibility in mast cells. We propose that Ikaros plays a similar role in T helper cells and is therefore a key factor controlling T helper cell differentiation. It is hypothesized that Ikaros'association with multiple cis-regulatory elements throughout the Th2 locus contributes to overall locus accessibility and governs IL-4 expressing potential in T cells. Using T cells from Iknull mice and strategies to suppress Ikaros function in wild type CD4+ T cells, the proposed experiments will characterize the role of Ikaros in conferring and maintaining Th2 locus accessibility in CD4+ T cells and determine its mechanism of action. The effects of modulating Ikaros expression on in vivo CD4+ T cell responses in EAE will also be examined. The proposal includes three specific aims: 1) To determine the role of Ikaros in regulating IL-4 expression """"""""potential"""""""" in T helper cells. 2) To invesitgate the mechanism of Ikaros-mediated regulation of Th2 cytokine locus accessbility in differentiated CD4+ T cells. 3) To examine the consequences of modulating Ikaros expression in T cells on disease progression in EAE. The results generated from the proposed experiments will contribute to understanding mechanisms governing Th1/Th2 differentiation. Such information is essential for the ultimate development of therapies that can manipulate effector pathways in disease such as MS where the CD4+ T cell response is highly polarized.
| Quirion, Mary R; Gregory, Gregory D; Umetsu, Sarah E et al. (2009) Cutting edge: Ikaros is a regulator of Th2 cell differentiation. J Immunol 182:741-5 |
