LYMPHOCYTES THAT SUPPRESS EAE

描述(改编自调查者摘要)：监管(抑制者) 淋巴细胞被认为在许多现象中发挥关键作用，从 移植耐受的自身免疫。然而，他们的机制是 由于系统的复杂性质，行动在很大程度上仍是未知的 学习。为了简化问题，调查人员已经生成了最低限度的 实验性自身免疫性脑脊髓炎小鼠模型的建立 多发性硬化症。他们已经产生了转基因小鼠(T/R+)，用于 编码人T细胞受体α链和β链的基因 脑脊髓性T细胞克隆。大多数T/R+小鼠没有 发展EAE。相反，当T/R+小鼠与RAG-1 KO小鼠杂交时， 产生T/R-小鼠，100%的T/R-子代患EAE 自然而然地。因为RAG-1突变阻止T/R小鼠 产生成熟的B和T淋巴细胞，这些小鼠唯一的淋巴细胞 含有抗MBP基因的T细胞。相比之下，T/R+还有 对于数量大致相同的抗MBP T细胞，一些是非转基因的 (内源性)具有不同谱系的α/βT细胞，以及 γ/增量T细胞和B细胞。因此，T/R-小鼠构成了单克隆性 可以向其添加定义的蜂窝组件及其 评估了EAE法规的重要性。调查人员的目标是 准确地理解这种调节是如何在细胞和 分子水平。他们想要确定淋巴细胞亚群 通过将T/R+小鼠与小鼠基因敲除的小鼠杂交来抵抗EAE 在T/R小鼠中只有一个淋巴间隔缺失，并通过注射 纯化(分选)细胞亚群进入T/R小鼠 EAE的发病。此外，他们还知道T/R+小鼠对EAE的抵抗力 既不是由于胸腺对MBP特异性的阳性选择失败所致 T细胞，也不是这些细胞的负性选择增加。 此外，两种动物外周淋巴器官中的抗MBP T细胞 不同类型的小鼠并不是无能的。为了更好地定义 调节细胞上有抗MBP的T细胞，它们也会比较抗MBP T细胞晚期T/R-鼠细胞与T/R+鼠细胞 反应，即在“关闭”期间，由激活引起的细胞死亡或其他 抗炎机制。最后，证明监管机构发挥作用的证据 EAE控制中的细胞也是通过过继转移诱导EAE提供的 抗MBP的CD4+Th2细胞。MBP特异性Th2细胞向RAG-1细胞的转移 KO或TCRαKO小鼠导致EAE的发展；然而，正常和 TCR Delta KO小鼠受体具有抵抗力。这强烈地表明 α/β细胞的存在可保护受者免受EAE的侵袭。这个 研究人员计划确定这些细胞的调控要求 对于特定的细胞类型，所需的最小细胞数 用于调节，以及这些细胞的特异性。具体目标是： 1)鉴定TCR+/RAG+小鼠的“保护性”T细胞亚群；2) 确定对正在进行的炎症反应的“抑制”是否 在RAG小鼠中发生改变，以及3)定义T细胞的数量 保护小鼠在Th2细胞转移后不会发生EAE。这个 提高了对此提供的负面调控的理解 定义的系统不仅可能适用于MS，而且还适用于其他 对自身免疫性疾病和一般耐受性知识的了解。

DESCRIPTION (Adapted from Investigator's abstract): Regulatory (suppressor) lymphocytes are assumed to play a key role in a number of phenomena, from autoimmunity to transplantation tolerance. However, their mechanism of action remains largely unknown due to the complex nature of the systems studied. To simplify matters, the investigators have generated a minimal mouse model of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. They have generated transgenic mice (T/R+) for the genes encoding the alpha and beta chains of the T-cell receptor from an encephalomyelitogenic T-cell clone. The majority of the T/R+ mice do not develop EAE. In contrast, when T/R+ mice were crossed with RAG-1 KO mice to generate T/R- mice, 100 percent of the T/R- progeny develop EAE spontaneously. Because the RAG-1 mutation prevents T/R- mice from generating mature B and T lymphocytes, the only lymphocytes these mice contain are anti-MBP transgenic T-cells. In contrast T/R+ have, in addition to roughly similar numbers of anti-MBP T-cells, some non transgenic (endogenous) alpha/beta T-cells with diverse repertoires, as well as gamma/delta T-cells and B-cells. Thus, T/R- mice constitute a monoclonal system to which defined cellular components can be added and their importance in EAE regulation assessed. The investigators' goal is to understand precisely how this regulation occurs at the cellular and molecular levels. They would like to identify the lymphocyte subpopulation responsible for EAE resistance by crossing T/R+ mice with mice knockout for only one of the lymphoid compartments lacking in T/R- mice, and by injecting purified (sorted) cell subpopulations into T/R- mice before and after the onset of EAE. In addition, they know that the EAE resistance of T/R+ mice is caused by neither a failure in thymic positive selection of MBP specific T-cells, nor an increased negative selection of these same cells. Furthermore, anti-MBP T-cells in the peripheral lymphoid organs of both types of mice are not anergic. In order to better define the action of regulatory cells on anti-MBP T-cells, they will also compare the anti-MBP cells of T/R- mice to those of T/R+ mice in the later stages of T-cell response, ie during "shut off", by activation induced cell death or other anti-inflammatory mechanisms. Finally, evidence for a role of regulatory cells in EAE control is also provided by EAE induction by adoptive transfer of anti-MBP CD4+ Th2 cells. Transfer of MBP specific Th2 cells into RAG-1 KO or TCR alpha KO mice results in EAE development; however, both normal and TCR delta KO mouse recipients are resistant. This strongly suggests that the presence of alpha/beta cells protects recipients against EAE. The investigators plan to define the requirements of these cells for regulation with regard to the specific cell type, the minimum number of cells necessary for regulation, and the specificity of such cells. The specific aims are: 1) To identify the "protective" T-cell subset in TCR+/RAG+ mice, 2) To determine whether the "suppression" of an ongoing inflammatory response is altered in RAG- mice, and 3) To define the population of T-cells that protects mice from developing EAE after transfer of Th2 cells. The increased understanding of negative regulation and control provided by this defined system is potentially applicable not only to MS, but also to other autoimmune diseases and to the knowledge of tolerance in general.