Contributions of CD8(+) T cells and viral spread to demyelinating disease

Acute and chronic demyelination are hallmarks of CNS infection by the neuro tropic JHM strain of mouse hepatitis virus. Although infectious virus is cl eared by CD8(+) T cells, both viral RNA and activated CD8(+) T cells remain in the CNS during persistence potentially contributing to pathology, To di ssociate immune from virus-mediated determinants initiating and maintaining demyelinating disease, mice were infected with two attenuated viral varian ts differing in a hypervariable region of the spike protein. Despite simila r viral replication and tropism, one infection was marked by extensive demy elination and paralysis, whereas the other resulted in no clinical symptoms and minimal neuropathology, Mononuclear cells from either infected brain e xhibited virus specific ex vivo cytolytic activity, which was rapidly lost during viral clearance. As revealed by class I tetramer technology the para lytic variant was superior in inducing specific CD8(+) T cells during the a cute disease. However, after infectious virus was cleared, twice as many vi rus-specific IFN-gamma-secreting CD8(+) T cells were recovered from the bra ins of asymptomatic mice compared with mice undergoing demyelination, sugge sting that IFN-gamma ameliorates rather than perpetuates JHM strain of mous e hepatitis virus-induced demyelination. The present data thus indicate tha t in immunocompetent mice, effector CD8(+) T cells control infection withou t mediating either clinical disease or demyelination. In contrast, demyelin ation correlated with early and sustained infection of the spinal cord. Rap id viral spread, attributed to determinants within the spike protein and po ssibly perpetuated by suboptimal CD8(+) T cell effector function, thus ulti mately leads to the process of immune-mediated demyelination.