Contributions of different subsets of T cells to coronavirus neuropathology

Mice infected with a coronavirus, the neurotropic strain JHM mouse hepatitis virus (MHV) develop disease ranging from chronic demyelination to fatal acute encephalitis. The diseases are largely immune-mediated and both CD8 and CD4 T cells are highly enriched in the central nervous system (CNS) at the peak of the immune response to the virus. Intracellular interferon-gamma (IFN-gamma) expression assays revealed that, while 50% of the CD8 T cells and 30% of the CD4 T cells in the infected CNS are virus-specific, the specificity of the remaining T cells remains unknown. These infiltrating cells, which are not specific for virus antigens or for any antigen in the CNS, are called bystander CD8 or CD4 T cells. Bystander CD8 T cells are able to induce demyelination in certain conditions, however, the mechanism of their actions is less well known. To study interferon gamma (IFN-gamma) as a possible mediator of bystander demyelination, irradiated mice were reconstituted with bone marrow from IFN-gamma-/- or IFN-gamma+/+ transgenic P14 mice. Thus, reconstituted mice had only bystander CD8 T cells which were either IFN-gamma-/- or IFN-gamma+/+, depending on the donor. Only chimeric mice reconstituted from donors IFN-gamma-+/+ developed demyelination, showing that the actions of bystander CD8 T cells are IFN-gamma mediated.; To study the role of epitope-specific CD4 T cells in JHM-induced acute encephalitis a recombinant virus was engineered with mutations in the immunodominant M133 epitope (rJ.MY135Q). Infection with this virus resulted in mild disease with no mortality. In addition, introduction of a CD4 T-cell epitope from Listeria monocytogenes into rJ.MY135Q restored an aggressive disease, showing the CD4 T cell response to a single epitope can be pathogenic. In mice inoculated with rJ.M Y135Q we determined increased number of regulatory T cells (Tregs) in the brain. Depletion of Tregs resulted in more aggressive disease with 50% mortality and adoptive transfer of Tregs in mice inoculated with recombinant JHMV increased their survival to 50%, demonstrating a role for Tregs in ameliorating the disease.