STAT4 regulation of effector CD4 T cells and CNS inflammation



 DESCRIPTION (provided by applicant): Multiple Sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that afflicts over two million individuals worldwide. While the etiology of MS remains unknown, it is clear that there is a genetic predisposition for the disease. Genome-wide association studies indicate a correlation between genetic variants of numerous inflammatory genes and disease susceptibility. Most recently, a susceptibility variant within the intronic sequence of the STAT4 gene was identified. Importantly, expression of the transcription factor STAT4 is essential for the development of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These data signify a potentially integral role for STAT4 during the pathogenesis of MS. Currently, the mechanism by which STAT4 mediates CNS inflammation remains elusive; however our own preliminary data show that CD4 T cell intrinsic expression of STAT4 is vital for EAE. Additionally, striking data from our laboratory demonstrates that STAT4 is required for accumulation of CD4 T cells in the inflamed CNS, as well as for the full array of CD4 T cell effector functions. Interestingly, CD4 T cells lacking expression of the IL-23 receptor complex exhibit many of the same characteristics of STAT4 deficient CD4 T cells, and the earliest reports published on IL-23 documented that it induced the phosphorylation of not only STAT3, but also STAT4. STAT4 is also known to regulate expression of IL-12Rß1, one component of the IL-23 receptor complex. Together, the published findings and our preliminary data lead us to hypothesize that IL-23 and STAT4 function in the same pathway in CD4 T cells during EAE, and that STAT4 governs the pathogenic signature in CD4 T cells necessary to confer encephalogenicity during CNS inflammation. To test this, we propose the following specific aims: Aim 1: To determine the impact of STAT4 expression on CD4 T cell functionality during CNS inflammation. Aim 2: To determine the prerequisite of intrinsic STAT4 expression for CD4 T cell accumulation during CNS inflammation. Aim 3: To determine the interplay between STAT4 signaling and the IL-23 pathway in CD4 T cells during CNS inflammation. Collectively, these studies are designed to provide new information regarding the cellular mediators of CNS inflammation during EAE and help to precisely define the properties and molecular regulators which control the development of encephalogenic CD4 T cells. Our long-term goal is elucidate the significance of STAT4 in promoting chronic inflammatory disorders, such as multiple sclerosis, in hopes that a transcriptional target will be identified which can be used for future therapeutic interventions.