Homeostatic Control and Retention of Virus Specific T Cells in the CNS

从激活的幼稚前体分化而来的记忆T细胞在多个组织中发挥免疫监视机制。这一机制在保护宿主不再与相同的Ag或病原体相遇方面起到了关键作用。一些记忆T细胞离开淋巴组织，进入非淋巴组织。然而，在中枢神经系统等非淋巴组织中控制T细胞动态平衡的机制尚未被探索。嗜神经性JHM病毒感染可诱导强烈的免疫应答，在此期间病毒特异性CDS T细胞迅速被募集到中枢神经系统并解决感染问题。然而，即使在传染性病毒被清除后，病毒RNA仍继续存在于中枢神经系统中，导致持续感染。在持续感染期间，T细胞保留在中枢神经系统中。然而，控制保留的机制还不是很清楚。这项提议的总体目标是探索CDS T细胞的作用机制 病毒持续感染期间中枢神经系统的滞留和维持。目的1确定在持续感染期间，抗原提呈是否诱导CDS T细胞滞留在中枢神经系统。这是基于发现保留在CNS中的CDS T细胞表现出激活的表型，并且这种保留与病毒的持久性直接相关。持续性病毒主要在少突胶质细胞中检测到。病毒抗原是直接提呈还是通过树突状细胞交叉提呈给CDS T细胞，将使用新产生的转基因小鼠品系进行检测。目的#2将测试CD4T细胞如何在持续感染期间对中枢神经系统CDS T细胞的动态平衡生存和保留做出贡献。这是基于CD4T细胞在促进CDS T细胞CNS渗透以及在持续感染期间提高CDS T细胞存活率方面的关键贡献。树突状细胞以及肿瘤坏死因子相关的凋亡诱导配体(TRAIL)在介导CDS T细胞的CD4帮助中的作用将在体内进行测试。此外，还将研究DC增强CDS T细胞存活的细胞机制。通过研究连接免疫的细胞相互作用，免疫提供了重要的体内平衡机制，控制T细胞在效应部位而不是淋巴组织中的滞留。

Memory T cells differentiated from the activated naive precursors exert immune surveillance mechanisms throughout multiple tissues. This mechanism provides a pivotal role in protecting the host from reencounter with the same Ag or pathogen. Some memory T cells leave lymphoid tissues and enter nonlymphoid tissues. However, mechanisms controlling T cell homeostasis in non-lymphoid tissues such as the CNS have not been explored. Infection of neurotropic JHM virus induces a robust immune response during which virus specific CDS T cells are rapidly recruited into the CNS and resolve the infection. Even after the infectious virus is cleared, however, viral RNA continues to exist in the CNS leading to persistent infection. T cells are retained in the CNS during persistent infection. However, mechanisms controlling the retention is not well understood. The overall goal of this proposal is to explore mechanisms contributing CDS T cell retention and maintenance in the CNS during virus mediated persistent infection. Aim #1 will determine whether Ag presentation induces CDS T cell retention in the CNS during persistent infection. It is based on the finding that CDS T cells retained in the CNS display an activated phenotype and the retention directly correlates with virus persistence. Persistent virus is mainly detected in oligodendrocytes. Whether viral Ag is directly presented or whether is cross-presented to CDS T cells by DCs will be examined using newly generated transgenic mouse lines. Aim #2 will test how CD4 T cells contribute to the homeostatic survival and retention of CDS T cells in the CNS during persistent infection. It is based on key contribution of CD4 T cells in facilitating CDS T cell CNS infiltration as well as in enhancing CDS T cell survival during persistent infection. The involvement of DCs as well as of TNF-related apoptosisinducing ligand (TRAIL) in mediating CD4 help to CDS T cells will be tested in vivo. Furthermore, cellular mechanisms by which DCs confer enhanced survival to CDS T cells will be examined. By investigating cellular interactions that link immune provide important homeostatic mechanisms controlling T cell retention within effector sites rather than lymphoid tissues.