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.

Public Health Relevance

Mechanisms of immune surveillance exerted by memory T lymphocytes within non-lymphoid tissues including the central nervous system are poorly understood. The goal of this project is to explore mechanisms by which antigen experienced T cells are retained and maintained in the CNS during virus mediated persistent infection

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS064932-04
Application #
8382530
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$261,461
Indirect Cost
$113,371
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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Phares, Timothy W; Stohlman, Stephen A; Hwang, Mihyun et al. (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416-27

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