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.
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
|Butchi, Niranjan B; Hinton, David R; Stohlman, Stephen A et al. (2014) Ifit2 deficiency results in uncontrolled neurotropic coronavirus replication and enhanced encephalitis via impaired alpha/beta interferon induction in macrophages. J Virol 88:1051-64|
|de Aquino, Maria Teresa P; Kapil, Parul; Hinton, David R et al. (2014) IL-27 limits central nervous system viral clearance by promoting IL-10 and enhances demyelination. J Immunol 193:285-94|
|Kapil, Parul; Stohlman, Stephen A; Hinton, David R et al. (2014) PKR mediated regulation of inflammation and IL-10 during viral encephalomyelitis. J Neuroimmunol 270:1-12|
|Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54|
|Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382-92|
|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|
|Puntambekar, Shweta S; Bergmann, Cornelia C; Savarin, Carine et al. (2011) Shifting hierarchies of interleukin-10-producing T cell populations in the central nervous system during acute and persistent viral encephalomyelitis. J Virol 85:6702-13|
|Savarin, Carine; Stohlman, Stephen A; Rietsch, Anna M et al. (2011) MMP9 deficiency does not decrease blood-brain barrier disruption, but increases astrocyte MMP3 expression during viral encephalomyelitis. Glia 59:1770-81|
|Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2010) Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis. J Immunol 185:5607-18|