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

嗜神经性鼠感染中枢神经系统（CNS） 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的多种效应，包括CD 8 + 细胞毒性T淋巴细胞（CTL）在预防病毒持续存在方面至关重要 和慢性脱髓鞘我们最近发现，缺乏CD 4 + JHMV感染后T细胞活化CTL数量减少， 大脑，这是与数量的显着增加， 经历程序性细胞死亡或凋亡的细胞。作为一个直接的延伸 这项工作，我们提出了一般假设，渗透和 在JHMV感染期间，CNS中CTL存活是依赖性的，至少在 部分作用于CD 4 + T细胞。该项目的首要目标是确定 CTL从外周血淋巴细胞向中枢神经系统浸润的机制 血管周围空间以及CD 4+细胞如何对其进行修饰。我们建议 CTL浸润通过分泌金属蛋白酶（MMP-7， MMP-9）和对趋化因子梯度（MIP-1 α，RANTES）的反应， 这些过程受到CD 4 + T细胞分泌产物的刺激， 细胞第二个目标是确定CTL 在JHMV感染小鼠的CNS中发生细胞凋亡，以及这是如何发生的。 由CD 4 + T细胞调节。我们认为CTL凋亡发生继发于 Fas介导的生长因子白细胞介素-2（IL-2）或 杀伤，与bcl-2水平降低相关的过程， T细胞耗竭进一步加重IL-2耗竭。大脑和 从正常小鼠和CD 4缺陷小鼠分离的CTL将被研究， 以及特定的突变株和转基因株。发病机理将是 通过特异性MMP的过度表达改变，细胞凋亡趋化因子- 使用缺陷性干扰载体系统的相关分子。结果 这些实验将提供一个更好的理解机制， 参与CTL贩运的特殊微环境中， 个脑袋

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.