CD4+ T cells play an important role in the immune response against viral infections. Here we propose to study two functions of CD4+ T cells with potential significance in neurological, demyelinating disease caused by the JHM strain of mouse hepatitis virus (JHMV). The first specific aim studies the role of cytotoxic CD4+ T cells in demyelination following JHMV infection, as well as its mechanism. The central hypothesis to be tested is that CD4+ CTL clear virus from oligodendrocytes, based on the fact that whereas total spleen cells affect virus in all brain cells, CD8+ CTL cannot clear virus from oligodendrocytes.
This aim will be accomplished by comparing the ability of CD4+ CTL and CD4+ not CTL to protect against fetal disease, and to reduce virus replication in the CNS, specifically in oligodendroglia. Furthermore, the frequency of CD4+ T cells with cytolytic activity versus total CD4+ T cells in the cerebral lymph nodes and brain will be determined. Finally the role of tumor necrosis factor (TNF) will be examined by preparing CD4+ CTL infected with a retrovirus synthesizing an anti-sense TNF gene. The rather unique demonstration of virus-specific CD4+ CTL may be related to the immunologically different environment of the brain. Due to its unique composition, the brain is more sensitive to inflammation than other tissues. Our preliminary data show that injection of either monoclonal antibodies to interleukin (IL)-4 and IL-10 at the time of infection, or a JHMV-specific Th1 clone well before infection, both precipitate a more severe acute disease, suggesting a modulating role of Th2 cells in CNS inflammation. The second specific aim addresses the hypothesis that the acute disease phase is mediated in part by the inflammatory Th1 subset of CD4+ cells, and that modulation of this response by the anti-inflammatory Th2 subset of CD4+ cells protects against immunopathology in the brain. However, modulation of the Th1 response by Th2 cells could have far-reaching consequences for the chronic stage of the disease.
This aim will be accomplished by the characterization of the cytokine patterns in brain during acute and early chronic infection, and examining the frequency of JHMV-specific Th1 and Th2 cells, as well as total CD4+ cells in brain and lymph nodes during acute and early chronic infection. Furthermore, the effect of manipulating Th2-cell induction on the disease course of JHMV-infected mice will be analyzed, in order to study the role of Th2 cells in CNS immunity.
|Kapil, Parul; Butchi, Niranjan B; Stohlman, Stephen A et al. (2012) Oligodendroglia are limited in type I interferon induction and responsiveness in vivo. Glia 60:1555-66|
|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|
|Savarin, Carine; Stohlman, Stephen A; Atkinson, Roscoe et al. (2010) Monocytes regulate T cell migration through the glia limitans during acute viral encephalitis. J Virol 84:4878-88|
|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|
|Phares, Timothy W; Ramakrishna, Chandran; Parra, Gabriel I et al. (2009) Target-dependent B7-H1 regulation contributes to clearance of central nervous system infection and dampens morbidity. J Immunol 182:5430-8|
|Zuo, Jun; Stohlman, Stephen A; Parra, Gabriel I et al. (2009) IL-15 independent maintenance of virus-specific CD8(+) T cells in the CNS during chronic infection. J Neuroimmunol 207:32-8|
|Savarin, Carine; Bergmann, Cornelia C (2008) Neuroimmunology of central nervous system viral infections: the cells, molecules and mechanisms involved. Curr Opin Pharmacol 8:472-9|
|Stohlman, S A; Hinton, D R (2001) Viral induced demyelination. Brain Pathol 11:92-106|
|Stohlman, S A; Bergmann, C; Cua, D et al. (1994) Location of antibody epitopes within the mouse hepatitis virus nucleocapsid protein. Virology 202:146-53|
|Strong, R K; Penny, D M; Feldman, R M et al. (1994) Engineering and expression of a secreted murine TCR with reduced N-linked glycosylation. J Immunol 153:4111-21|