THE ROLE OF CD4 CELLS IN THE TRAFFICKING OF CTLS IN CNS TISSUE

嗜神经性小鼠对中枢神经系统的感染 冠状病毒JHMV导致急性脑脊髓炎，原发性脱髓鞘 、敏感株持续感染。彻底消除 病毒在急性感染过程中由包括CD8+在内的多种效应物 细胞毒性T淋巴细胞(CTL)是防止病毒持续存在的关键 和慢性脱髓鞘。我们最近的研究表明，CD4+的缺失 JHMV感染小鼠T细胞后活化的CTL数量减少 大脑，这与脑细胞数量显著增加有关 正在经历细胞程序性死亡或凋亡的细胞。作为一种直接延伸 在这项工作中，我们提出了普遍的假设，即渗透和 JHMV感染期间CNS中CTL的存活是依赖的，至少在 部分，对CD4+T细胞的影响。该项目的第一个目标是确定 CTL从中枢神经系统向中枢神经系统组织渗透的机制 血管周围空间，以及CD4+细胞如何改变这一空间。我们建议 细胞毒性T淋巴细胞(CTL)的浸润是通过分泌金属蛋白酶(MMP7， 对趋化因子梯度(MIP-1α、RANTES)和 这些过程是由CD4+T细胞的分泌产物刺激的 细胞。第二个目标将是确定CTL JHMV感染小鼠中枢神经系统细胞凋亡及其机制 由CD4+T细胞调节。我们认为CTL细胞的凋亡继发于 Fas介导的生长因子白介素2(IL-2)缺失 杀伤，与bcl2和CD4+水平降低相关的过程 T细胞枯竭进一步加剧了IL-2的枯竭。大脑和大脑 从正常小鼠和CD4缺陷小鼠分离的CTL将被研究为 以及特定的突变株和转基因株。发病机制将是 受特定基质金属蛋白酶、细胞凋亡趋化因子过度表达的影响- 相关分子使用有缺陷的干扰载体系统。结果是 这些实验将提供对机制的更好理解 在联合国专门的微环境内参与CTL贩运 大脑。

Infection of the central nervous system (CNS) with the neurotropic murine coronavirus JHMV results in acute encephalomyelitis, primary demyelination , and persistent infection in susceptible strains. Complete elimination of virus during the acute infection by multiple effectors including CD8+ cytotoxic T lymphocytes (CTL), is critical in preventing viral persistence and chronic demyelination. We have recently shown that the absence of CD4+ T cells in JHMV infection results in decreased numbers of activated CTL in the brain and this is associated with a marked increase in the number of cells undergoing programmed cell death or apoptosis. As a direct extension of this work, we propose the general HYPOTHESIS that the infiltration and survival of CTL in CNS during JHMV infection is dependent, at least in part, upon CD4+ T cells. The first aim of the project will be to determine the mechanism by which CTL infiltrate into CNS tissue from the perivascular space and how this is modified by CD4+ cells. We suggest that CTL infiltration is increased by secretion of metalloproteinases (MMP-7, MMP-9) and in response to chemokine gradients (MIP-1alpha, RANTES) and that these processes are stimulated by the secreted products of CD4+ T cells. The second aim will be to determine the mechanism by which CTL undergo apoptosis in the CNS of JHMV-infected mice and how this is modulated by CD4+ T cells. We suggest apoptosis of CTL occurs secondary to deletion of the growth factor interleukin-2 (IL-2) OR by Fas-mediated killing, processes associated with decreased levels of bcl-2 and that CD4+ T cell depletion further accentuates IL-2 depletion. Both brains and isolated CTL from normal mice and CD4-deficient mice will be studied as well as specific mutant and transgenic strains. Pathogenesis will be altered by over expression of specific MMP, chemokines of apoptosis- related molecules using a Defective Interfering vector system. The results of these experiments will provide a better understanding of the mechanisms involved in CTL trafficking within the specialized microenvironment of the brain.