THE ROLE OF CD4 CELLS IN THE TRAFFICKING OF CTLS IN CNS TISSUE

点击翻译按钮获取中文摘要

Infection of the central nervous system (CNS) with the neurotropic murine coronavirus JHMV results in acute encephalomyelitis, primary demyelination , and persistent infection in susceptible strains. Complete elimination of virus during the acute infection by multiple effectors including CD8+ cytotoxic T lymphocytes (CTL), is critical in preventing viral persistence and chronic demyelination. We have recently shown that the absence of CD4+ T cells in JHMV infection results in decreased numbers of activated CTL in the brain and this is associated with a marked increase in the number of cells undergoing programmed cell death or apoptosis. As a direct extension of this work, we propose the general HYPOTHESIS that the infiltration and survival of CTL in CNS during JHMV infection is dependent, at least in part, upon CD4+ T cells. The first aim of the project will be to determine the mechanism by which CTL infiltrate into CNS tissue from the perivascular space and how this is modified by CD4+ cells. We suggest that CTL infiltration is increased by secretion of metalloproteinases (MMP-7, MMP-9) and in response to chemokine gradients (MIP-1alpha, RANTES) and that these processes are stimulated by the secreted products of CD4+ T cells. The second aim will be to determine the mechanism by which CTL undergo apoptosis in the CNS of JHMV-infected mice and how this is modulated by CD4+ T cells. We suggest apoptosis of CTL occurs secondary to deletion of the growth factor interleukin-2 (IL-2) OR by Fas-mediated killing, processes associated with decreased levels of bcl-2 and that CD4+ T cell depletion further accentuates IL-2 depletion. Both brains and isolated CTL from normal mice and CD4-deficient mice will be studied as well as specific mutant and transgenic strains. Pathogenesis will be altered by over expression of specific MMP, chemokines of apoptosis- related molecules using a Defective Interfering vector system. The results of these experiments will provide a better understanding of the mechanisms involved in CTL trafficking within the specialized microenvironment of the brain.