Potential role of CD4(+) T cell-mediated apoptosis of activated astrocytesin Theiler's virus-induced demyelination

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV ) into susceptible mouse strains results in a chronic, immune-mediated demy elinating disease similar to human multiple sclerosis, Here, we examined th e role of astrocytes as an APC population in TMEV-induced demyelination and assessed the potential consequences of T cell activation following Ag pres entation. IFN-gamma-pretreated astrocytes were able to process and present all the predominant T cell epitopes of TMEV to virus-specific T cell hybrid omas, clones, as well as bulk T cells. Despite low levels of proliferation of T cells due to prostaglandins produced by astrocytes, such Ag presentati on by activated astrocytes induced the production of IFN-gamma, a represent ative proinflammatory cytokine, in TMEV-specific Th cell clones derived fro m the CNS of virus-infected mice. Furthermore, these Th cell clones mediate lysis of the astrocytes in vitro in a Fas-dependent mechanism. TUNEL stain ing of CNS tissue demonstrates the presence of apoptotic GFAP(+) cells in t he white matter of TMEV-infected mice. These results strongly suggest that astrocytes could play an important role in the pathogenesis of TMEV-induced demyelination by activating T cells, subsequently leading to T cell-mediat ed apoptosis of astrocytes and thereby compromising the blood-brain barrier .