The T cell inhibitory ligand B7-H1 hinders T cell-mediated virus control, but also ameliorates clinical disease during autoimmune and virus-induced CNS disease. In mice infected with gliatropic demyelinating coronavirus, B7-H1 expression on oligodendroglia delays virus control, but also dampens clinical disease. To define the mechanisms by which B7-H1 alters pathogenic outcome, virus-infected B7-H1-deficient (B7-H1(-/-)) mice were analyzed for altered peripheral and CNS immune responses. B7-H1 deficiency did not affect peripheral T or B cell activation or alter the magnitude or composition of CNS-infiltrating cells. However, higher levels of IFN-γ mRNA in CNS-infiltrating virus-specific CD8 T cells as well as CD4 T cells contributed to elevated IFN-γ protein in the B7-H1(-/-) CNS. Increased effector function at the single-cell level was also evident by elevated granzyme B expression specifically in virus-specific CNS CD8 T cells. Although enhanced T cell activity accelerated virus control, 50% of mice succumbed to infection. Despite enhanced clinical recovery, surviving B7-H1(-/-) mice still harbored persisting viral mRNA, albeit at reduced levels compared with wild-type mice. B7-H1(-/-) mice exhibited extensive loss of axonal integrity, although demyelination, a hallmark of virus-induced tissue damage, was not increased. The results suggest that B7-H1 hinders viral control in B7-H1 expressing glia cells, but does not mediate resistance to CD8 T cell-mediated cytolysis. These data are the first, to our knowledge, to demonstrate that B7-H1-mediated protection from viral-induced immune pathology associated with encephalomyelitis resides in limiting T cell-mediated axonal bystander damage rather than direct elimination of infected myelinating cells.
Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis.