T cell activation requirement in autoimmune demyelination

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是一种T细胞介导的自身免疫性疾病，其特征为中枢神经系统（CNS）炎症和脱髓鞘，其特征令人联想到人类疾病多发性硬化症（MS）。在EAE模型的先前工作表明，致病性T细胞是一个分泌细胞因子的Th 1表型，如干扰素-？和光敏素。最近，已经提出分泌细胞因子IL-17的T细胞亚群也是致病的。令人感兴趣的是，已经发现IL- 17在MS病变中的表达增加。本课题组一直对EAE中控制T细胞分化的转录因子和T细胞的致病性感兴趣。我们和其他人最近发现转录因子T-bet似乎在EAE的发生中非常重要。虽然这种转录因子对于Th 1分化是必不可少的，但其在产生IL-17的T细胞的发育中的作用是有争议的。已经表明，产生IL-17的T细胞在T-bet缺陷小鼠中增加，但这些小鼠对EAE的发展具有抗性。转化生长因子-β（一种长期以来被认为具有免疫调节作用的细胞因子）可能是IL-17 T细胞分化的重要细胞因子，这一观察结果进一步加剧了这些观察结果。基于我们先前在T细胞分化方面的工作，我们将测试以下假设：产生IL-17的T细胞有几种亚型，并且那些致病性的T细胞基于其转录谱引起非常特定类型的炎症。特别是，在缺乏IFN-γ/IFN-γ的情况下产生的IL-17产生T细胞，STAT 1信号转导诱导严重的疾病与中性粒细胞募集，人类疾病的特征，视神经肌病。预计通过了解控制T细胞致脑炎性的分子机制，我们将能够为人类炎症性疾病（如MS）设计更合理的治疗方法。在这个提议中，我们将研究负责Th 1和Th 17淋巴细胞分化的转录因子，重点在于确定致病或致脑炎表型所必需的转录因子。此外，我们还将检测多发性硬化患者产生IL-17的T细胞的情况，并确定目前的免疫调节疗法是否影响这种细胞因子的分泌。

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.