Regulatory T cells in MBP-Specific Autoimmunity

描述（由申请人提供）：多发性硬化症（MS）是一种 中枢神经系统的炎性脱髓鞘疾病， 据信是由于自身反应性T细胞特异性 髓磷脂抗原实验性变态反应性脑脊髓炎（EAE）是一种动物 通过用髓磷脂抗原免疫诱导的MS模型。在 EAE易感的B10.PL菌株，研究集中在对EAE易感的B10.PL菌株特异性的T细胞上。 髓鞘碱性蛋白（MBP）的免疫显性表位，AcMBP 1 -11。我们以前的 研究表明，AcMBP 1 -11的免疫优势是免疫的产物， MBP内源性表达诱导的耐受。我们演示了使用 MBP缺陷型小鼠中，MBP 121 -150是MBP中最具免疫原性的区域。 缺乏宽容。MBP 121 -150特异性T细胞在野生型中是亚显性的。 因为中枢耐受机制消除了大部分，但不是全部， 外周血T细胞。使用MBP 121 -150特异性T细胞受体 在转基因小鼠模型中，我们发现， 逃避中枢耐受是致病的，因为它们可以特异性地 引发EAE。新的数据显示，转基因 位于外周的MBP 121 -150特异性T细胞被阻止， 通过调节性T细胞引起自发性疾病。的过继转移 转基因、幼稚MBP 121 -150特异性T细胞植入T细胞缺陷小鼠 导致快速和严重的自身免疫性疾病。这种自身免疫完全是 通过引入CD 4 + T细胞来预防。令人惊讶的是，调节性T细胞 在转移后不抑制MBP特异性T细胞的体内扩增，或 它们向大脑的迁移。该提案的重点是定义表型 (Aim 1）和调节性T细胞的作用机制（目的2）。我们将 检验调节性T细胞改变细胞因子环境的假设， 抑制Th 1炎性T细胞的活化。 了解调节性T细胞如何防止MBP特异性T细胞 介导疾病对于理解MS的发病机制很重要， 提供新的治疗策略的见解。

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.