T cell activation requirement in autoimmune demyelination

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DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a T cell mediated, autoimmune disorder characterized by central nervous system (CNS) inflammation and demyelination, features reminiscent of the human disease, multiple sclerosis (MS). Prior work in the EAE model has suggested that the pathogenic T cell is one that secretes cytokines of the Th1 phenotype, such as interferon-? and lymphotoxin. Recently, it has been suggested that a subset of T cells that secrete the cytokine IL-17 are also pathogenic. Of interest, IL- 17 has been found to be increased in expression in MS lesions. Our group has been interested in the transcription factors that control T cell differentiation in EAE and the pathogenicity of T cells. We and others recently showed that the transcription factor T- bet appears to be very important in the development of EAE. While this transcription factor is essential for Th1 differentiation, its role in the development of IL-17-producing T cells is controversial. It has been shown that IL-17-producing T cells are increased in T-bet-deficient mice, yet these mice are resistant to the development of EAE. These observations are further compounded by the observation that transforming growth factor- beta, a cytokine long thought to be immunoregulatory, may be an important cytokine for the differentiation of IL-17 T cells. Building on our prior work in T cell differentiation, we will test the hypothesis that there are several subtypes of IL-17-producing T cells, and that those that are pathogenic elicit very specific types of inflammation based on their transcriptional profile. In particular, IL-17-producing T cells produced in the absence of IFN-?/STAT1 signaling induce severe disease with neutrophil recruitment, features of the human disease, neuromyelitis optica. It is anticipated that by understanding the molecular mechanisms that control T cell encephalitogenicity, we will be able to design more rational therapies for human inflammatory diseases such as MS. PUBLIC HEALTH RELEVANCE: In this proposal, we will examine the transcription factors that are responsible for the differentiation of Th1 and Th17 lymphocytes, with an emphasis on determining the transcription factors necessary for a disease causing or encephalitogenic phenotype. In addition, we will examine the production of IL-17-producing T cells from patients with multiple sclerosis and determine whether the current immunomodulatory therapies affect secretion of this cytokine.