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

从被激活的原始前体分化出来的记忆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次遇到相同的银或病原体方面发挥了关键作用。一些记忆T细胞离开淋巴组织进入非淋巴组织。然而，在非淋巴组织如中枢神经系统中控制T细胞稳态的机制尚未被探索。嗜神经性JHM病毒感染可诱导强烈的免疫反应，在此过程中，病毒特异性CDS T细胞被迅速招募到中枢神经系统并解决感染。然而，即使在感染病毒被清除后，病毒RNA仍继续存在于中枢神经系统中，导致持续感染。T细胞在持续感染期间保留在中枢神经系统中。然而，控制保留的机制尚不清楚。本提案的总体目标是探索CDS T细胞的机制

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.