Antigen presention by glial cells in stimulating T cells

中枢神经系统(CNS)内T细胞介导的免疫反应通过清除感染源是有益的，但通过激活常驻细胞和破坏组织也是有害的，从而导致免疫病理学。在病毒和自身抗原诱导的炎症过程中，触发T细胞效应器功能的一个重要因素是识别中枢神经系统内主要组织相容性抗原(MHC)提出的同源抗原(Ag)。因此，对中枢神经系统内MHC表达的严格调控是疾病进展的关键决定因素。这项建议检查了由嗜神经性JHM病毒建立的急性和持续病毒感染期间MHC依赖的T细胞调节，JHM病毒是冠状病毒科的成员。尽管T细胞的急性感染得到了控制，但其后果是与病毒持久性相关的持续慢性脱髓鞘 以非传染性核糖核酸的形式。这种病毒对各种类型的中枢神经系统细胞的趋向性为分析单个胶质细胞对抗原提呈和T细胞刺激的贡献提供了一个独特的模型。我们的总体假设是，与不同的神经胶质细胞群体的相互作用导致了关于CD8+T细胞的激活、存活和发病机制的不同结果。目的1研究I型和II型干扰素在体内急性病毒感染过程中诱导神经胶质细胞亚群MHC I、II类表达的作用。目的2验证I类/CD8+T细胞相互作用是通过分泌干扰素-γ增强小胶质细胞II类表达的假说。这是基于观察到驻留的CNS细胞上的I类表达先于II类表达。目的3评估神经胶质细胞的能力 在急性感染期间刺激CD8+T细胞的亚群。银离子的相对提呈能力 在炎症的不同阶段，将使用高度敏感的病毒特异性T细胞杂交瘤和体内T细胞转移来评估少突胶质细胞、星形胶质细胞和小胶质细胞。目的4探讨病毒持久性、抗原提呈和干扰素-γ/RANTES分泌在介导T细胞在中枢神经系统内滞留中的相关性。转基因技术，特别是在不同胶质细胞中表达绿色荧光蛋白(GFP)的小鼠，以及流式细胞术将被用于表征体内T细胞和不同胶质细胞之间的相互作用。这项建议的目标是描述单个胶质细胞类型在以MHC依赖的方式调节CD8+和CD4+T细胞方面的作用。具体地说，少突胶质细胞和星形胶质细胞在体内以抗原特异的方式与CD8+T细胞相互作用的倾向将被揭示。最后，将确定在持续期间调节T细胞分泌细胞因子/趋化因子的机制，从而潜在地促进慢性脱髓鞘。

T cell mediated immune responses within the central newous system (CNS) are beneficial by clearing infectious agents, but are also detrimental by activating resident cells and destroying tissue, leading to immunopathogy. A vital force in triggering T cell effector function both during virus and auto-Ag induced inflammation is recognition of cognate antigen (Ag) presented by major histocompatibility antigens (MHC) within the CNS. Strict regulation of MHC expression within the CNS is thus a critical determinant in disease progression. This proposal examines MHC dependent T cell regulation during acute and persistent viral infection established by the neurotropic JHM virus, a member of the coronaviridae. Despite control of acute infection by T cells, the consequences are ongoing chronic demyelination associated with virus persistence in the form of noninfectious RNA. The tropism of this virus for a variety of CNS cell types provides a unique model to analyze the contribution of individual glial cells to Ag presentation and T cell stimulation. Our overall hypothesis is that interactions with distinct glial cell populations result in heterologous outcomes with respect to CD8 + T cell activation, suwival and pathogenesis. Aim 1 examines the role of type I versus type II interferons in inducing MHC class I and class II expression on glial cell subsets during acute virus infection in vivo. Aim 2 tests the hypothesis that class I/CD8+ T cell interactions are critical in augmenting class II expression on microglia via secretion of IFN-gamma. This is based on the observation that class I expression precedes class II expression on resident CNS cells. Aim 3 evaluates the ability of glial cell subsets to stimulate CD8+ T cells during acute infection. Relative Ag presentation capacities of oligodendrocytes, astrocytes and microglia during distinct stages of inflammation will be assessed using highly sensitive virus specific T cell hybridomas in and T cell transfers in vivo. Aim 4 addresses the correlation between viral persistence, Ag presentation, and IFN-gamma/RANTES secretion in mediating retention of T cells within the CNS. Transgenic technology, specifically mice expressing green fluorescent protein (GFP) in distinct glial cells, and flow cytometry will be used to characterize interactions between T cells and distinct glial cells in vivo. The goals of this proposal are to delineate contributions of individual glial cell types in regulating CD8+ and CD4+ T cells in a MHC-dependent manner. Specifically the propensity of oligodendrocytes and astrocytes to interact with CD8+ T cells in an Ag specific manner in vivo will be revealed. Lastly, the mechanisms regulating T cell secretion of cytokine/chemokine during persistence, thus potentially contributing to chronic demyelination, will be defined.