Regulatory T cells in MBP-Specific Autoimmunity

描述(申请人提供)：多发性硬化症(MS)是一种 中枢神经系统炎症性脱髓鞘疾病 被认为是由于自身反应性T细胞特异性的错误激活所致 寻找髓鞘抗原。实验性变态反应性脑脊髓炎是一种 髓鞘抗原免疫诱导的多发性硬化症模型。在 易感EAE的B10.PL株，研究重点是针对EAE的特异性T细胞 髓鞘碱性蛋白的免疫优势表位AcMBP1-11。我们以前的 研究表明，AcMBP1-11的免疫优势是免疫的产物 内源性表达MBP诱导的耐受。我们演示了使用 MBP缺陷小鼠认为MBP121-150是MBP在小鼠体内免疫原性最强的区域 缺乏宽容。野生型中MBP121-150特异性T细胞占优势 小鼠，因为中枢耐受机制消除了大部分，但不是全部 外周血中的T细胞。使用MBP121-150特异性T细胞受体 转基因小鼠模型，我们发现MBP121-150特异性T细胞 逃避中枢耐受是致病的，因为它们可以特定地 触发以诱发EAE。这里提供的新数据表明，转基因 驻留在外围的MBP121-150特异性T细胞被阻止 通过调节性T细胞导致自发性疾病。领养转让 转基因单纯的MBP121-150特异性T细胞进入T细胞缺陷小鼠 导致迅速而严重的自身免疫性疾病。这种自体免疫完全是 通过引入CD4+T细胞来预防。令人惊讶的是，调节性T细胞 转移后不抑制体内MBP特异性T细胞的扩增 它们迁移到大脑。这项建议的重点是定义表型 (目标1)和调节T细胞的作用机制(目标2)。我们会 检验调节性T细胞改变局部细胞因子环境的假设 抑制Th1炎性T细胞的活化。 了解调节性T细胞如何阻止MBP特异性T细胞 介导性疾病对于理解MS的发病机制很重要，可能 为新的治疗策略提供见解。

DESCRIPTION (provided by the applicant): Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system that is believed to result from erroneous activation of self-reactive T cells specific for myelin antigens. Experimental allergic encephalomyelitis (EAE) is an animal model for MS that is induced by immunization with myelin antigens. In the EAE-susceptible B10.PL strain, research has focused on T cells specific for the immunodominant epitope of myelin basic protein (MBP), AcMBP1-11. Our previous studies showed that the immunodominance of AcMBP1-11 is the product of immune tolerance induced by endogenous expression of MBP. We demonstrated using MBP-deficient mice that MBP121-150 is the most immunogenic region of MBP in the absence of tolerance. MBP121-150-specific T cells are subdominant in wild-type mice because central tolerance mechanisms eliminate most, but not all, of these T cells from the periphery. Using a MBP121-150-specific T cell receptor transgenic mouse model, we showed that the MBP121-150-specific T cells that escape central tolerance are pathogenic because they can be specifically triggered to induce EAE. New data presented here show that transgenic MBP121-150-specific T cells that reside in the periphery are prevented from causing spontaneous disease by regulatory T cells. Adoptive transfer of transgenic, naive MBP121-150-specific T cells into T cell deficient mice results in rapid and severe autoimmune disease. This autoimmunity is completely prevented by introducing CD4+ T cells. Surprisingly, the regulatory T cells do not inhibit expansion of the MBP-specific T cells in vivo after transfer or their migration to the brain. This proposal focuses on defining the phenotype (Aim 1) and mechanisms of action (Aim 2) of the regulatory T cells. We will test the hypothesis that regulatory T cells alter the cytokine milieu at sites of antigen presentation to inhibit activation of Th1 inflammatory T cells. Understanding how regulatory T cells prevent MBP-specific T cells from mediating disease is important for understanding the pathogenesis of MS and may provide insights into new therapeutic strategies.