Effector-Regulator Immune Interactions During Autoimmune Demyelinating Disease

多发性硬化症(MS)是一种炎症性、脱髓鞘的中枢神经系统(CNS)疾病 影响着美国100多万人。T细胞驱动的免疫病理学是MS和其他疾病的中心特征 免疫介导的疾病。因此，这些致病T细胞反应的免疫调节是 这是获得自身免疫力的一个重要探索。长期以来，我们一直对免疫基础感兴趣 人类多发性硬化症(MS)及其动物模型(EAE)的研究。而CD4T细胞的致病作用很好 在这些疾病中，来自我们和其他人的越来越多的证据表明CD8 T细胞在这些疾病中发挥了作用 疾病。通过对MS和EAE的研究，我们证明了CD8对关键疾病的调节作用 疾病中的T细胞。对这些细胞在下调其他自身免疫中的作用的类似认识 疾病也出现了。我们还发现与MS复发相关的CD8的抑制活性 T细胞可以通过特定的细胞因子在体外进行预处理来恢复，显示了T细胞的功能可塑性。 并为治疗干预提供了一条潜在的途径。同时，它也是 越来越清楚的是，严重的自身免疫性疾病的特征是对 效应/致病的CD4T细胞对免疫的调节。总的来说，这些研究强调了 了解CD4效应者T细胞抵抗抑制的生物学意义 CD8抑制及其调控的错综复杂。我们的建议很难解决这一问题 在Our女士的背景下，我们了解免疫调节机构的基本特征 最近的研究展示了CD4-CD8效应-调节动力学的几个新方面，并基于 这些发现，我们假设来自MS患者的CD4T细胞具有内在的增强趋势 在炎症环境中产生免疫抑制的效应器抵抗，而多发性硬化症的CD8T细胞 患者有一种内在增强的倾向，即发展出较低的抑制能力。我们还假设 这些表型是塑料的，可以通过适当的刺激进行调节。为了解决这些假设， 我们将使用双管齐下的方法：(1)我们将解决多发性硬化症中CD4抵抗的生物学和调节 在自身免疫性疾病的背景下获得对这些过程的直接见解。这一目标的一部分还将 重点关注IL-17细胞因子的新的CD4内在生物学，如我们最近的出版物所展示的；以及(2) 我们还将讨论多发性硬化症中CD8抑制的生物学和调制。这些研究将提供 对MS发病机制背后的免疫失调的重要见解，以及对 多发性硬化症和多种其他疾病环境中的治疗方法。

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) that affects over 1 million people in the US. T-cell-driven immunopathology is a central feature of MS and other immune-mediated diseases. As a consequence, the immune regulation of these pathogenic T-cell responses is an important quest in the approach to autoimmunity. We have had a long-standing interest in the immune basis of human multiple sclerosis (MS) and its animal model (EAE). While the pathogenic role of CD4 T-cells is well established in these diseases, there is growing evidence from us and others for a role of CD8 T-cells in these diseases. Through studies in MS and EAE, we have demonstrated the critical disease regulatory role of CD8 T-cells in disease. Similar appreciation for the role of these cells in downregulating other autoimmune diseases has also emerged. We have also shown that the suppressor activity of MS relapse-associated CD8 T-cells can be restored by in vitro pre-treatment with specific cytokines, revealing functional plasticity of these cells and providing a potential avenue for therapeutic intervention. At the same time, it is also becoming clear that severe autoimmune disease is characterized by increased resistance of effector/pathogenic CD4 T-cells to immune regulation. Collectively, these studies underscore the importance of understanding both the biology of CD4 effector T-cell resistance to suppression as well as the intricacies of CD8 suppression and its modulation. Our proposal addresses this poorly understood but fundamental feature of the immune regulatory apparatus, in the context of MS. Our recent studies demonstrate several novel aspects of the CD4-CD8 effector-regulator dynamics and based on these findings, we hypothesize that CD4 T-cells from MS patients have an intrinsically enhanced tendency to develop effector resistance to immune suppression in an inflammatory context, while CD8 T-cells from MS patients have an intrinsically enhanced tendency to develop lower suppressive ability. We also hypothesize that these phenotypes are plastic and can be modulated by appropriate stimuli. To address these hypotheses, we will use a two-pronged approach: (1) We will address the biology and modulation of CD4 resistance in MS to gain direct insights into these processes in the context of autoimmune disease. A part of this aim will also focus on the novel CD4-intrinsic biology of IL-17 cytokines, as demonstrated in our recent publication; and (2) We will also address the biology and modulation of CD8 suppression in MS. These studies will provide important insights into the immune dysregulation that underlies MS pathogenesis, with implications for treatment approaches in MS and multiple other disease settings.