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

从活化的幼稚前体分化的记忆T细胞在多个组织中发挥免疫监视机制。这种机制在保护宿主避免再次遇到相同的抗原或病原体方面发挥了关键作用。一些记忆T细胞离开淋巴组织并进入非淋巴组织。然而，在非淋巴组织如CNS中控制T细胞稳态的机制尚未被探索。嗜神经性JHM病毒的感染诱导强烈的免疫应答，在此期间病毒特异性CDS T细胞被快速募集到CNS中并解决感染。然而，即使在感染性病毒被清除后，病毒RNA仍继续存在于CNS中，导致持续感染。T细胞在持续感染期间保留在CNS中。然而，控制保留的机制还不清楚。本提案的总体目标是探索CDS T细胞的作用机制， 在病毒介导的持续感染期间在CNS中的保留和维持。目的#1将确定持续感染期间Ag呈递是否诱导CNS中的CDS T细胞滞留。这是基于以下发现：保留在CNS中的CDS T细胞显示活化的表型，并且保留与病毒持久性直接相关。持久性病毒主要在少突胶质细胞中检测到。将使用新产生的转基因小鼠系检查病毒Ag是否直接呈递或是否通过DC交叉呈递给CD8 T细胞。目标#2将测试在持续感染期间，CD4 T细胞如何有助于CNS中CD8 T细胞的稳态存活和保留。它是基于CD4 T细胞在促进CDS T细胞CNS浸润以及在持续感染期间增强CDS T细胞存活中的关键贡献。将在体内测试DC以及TNF相关的肿瘤坏死诱导配体（TRAIL）在介导CD4辅助CD8 T细胞中的参与。此外，将检查DC赋予CDS T细胞增强的存活的细胞机制。通过研究连接免疫的细胞相互作用，提供了重要的稳态机制，控制T细胞在效应位点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.