Antigen presention by glial cells in stimulating T cells

中枢新生系统（CNS）内的T细胞介导的免疫应答通过清除感染因子是有益的，但也通过激活驻留细胞和破坏组织而有害，导致免疫病理学。在病毒和自身抗原诱导的炎症期间触发T细胞效应器功能的重要力量是识别CNS内由主要组织相容性抗原（MHC）呈递的同源抗原（Ag）。因此，CNS内MHC表达的严格调节是疾病进展的关键决定因素。该提案研究了由嗜神经性JHM病毒（冠状病毒科成员）建立的急性和持续性病毒感染期间MHC依赖性T细胞的调节。尽管通过T细胞控制了急性感染，但其后果是与病毒持续存在相关的持续慢性脱髓鞘 以非感染性RNA的形式存在。该病毒对多种CNS细胞类型的嗜性提供了一个独特的模型来分析单个胶质细胞对Ag呈递和T细胞刺激的贡献。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异源性结果，就CD 8 + T细胞活化，suwival和发病机制。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胶质细胞亚群表达MHC I类和II类的作用。目的2检验I类/CD 8 + T细胞相互作用在通过分泌IFN-γ增强小胶质细胞上的II类表达中至关重要的假设。这是基于在驻留CNS细胞上I类表达先于II类表达的观察。目的3评价胶质细胞的功能 在急性感染期间刺激CD 8 + T细胞。相对抗原呈递能力 将使用高度敏感的病毒特异性T细胞杂交瘤和体内T细胞转移来评估炎症的不同阶段期间的少突胶质细胞、星形胶质细胞和小胶质细胞。目的4阐明病毒持续存在、抗原呈递和IFN-γ/RANTES分泌在介导CNS内T细胞滞留中的相关性。转基因技术，特别是在不同的神经胶质细胞中表达绿色荧光蛋白（GFP）的小鼠，和流式细胞术将用于表征体内T细胞和不同的神经胶质细胞之间的相互作用。该建议的目标是描绘在调节CD 8+和CD 4 + T细胞的MHC依赖性的方式的个别神经胶质细胞类型的贡献。具体地，将揭示少突胶质细胞和星形胶质细胞在体内以Ag特异性方式与CD 8 + T细胞相互作用的倾向。最后，将定义在持久性期间调节T细胞分泌细胞因子/趋化因子的机制，从而可能导致慢性脱髓鞘。

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.