STUDY OF THE MECHANISMS BY WHICH CD4-CELLS CONTRIBUTE TO PROTECTION IN THEILER MURINE ENCEPHALOMYELITIS( T)

Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus whic h causes a biphasic central nervous system (CNS) disease in certain st rains of mice. Lytic virus replication within the CNS causes acute dam age at early times post-infection, with the surviving animals developi ng a chronic CNS demyelinating disease. This damage is thought to resu lt both from direct viral damage and from an immunopathological CD4+ T -cell mediated delayed-type hypersensitivity response to virus. By con trast, CD4+ T cells have a vital protective role at early times post-i nfection, as mice specifically depleted of CD4+ T cells of this subset prior to infection with TMEV die within 3-5 weeks. In an investigatio n of how CD4+ T cells act to mediate protection in TMEV-infected mice, we show that CD4+ cell-depleted animals, which fail to make a signifi cant antiviral antibody response, could be protected by passive transf er of neutralizing antibodies. However, surviving animals had high lev els of persisting virus in the CNS and they developed very severe symp toms of chronic demyelinating disease. The appearance of infectious vi rus was not due to selection of neutralizing antibody-resistant viral variants. These results demonstrate that the key protective role of CD 4+ T cells in TMEV-infected mice is to provide help for antibody produ ction by B cells at early times post-infection, but that other CD4+ ce ll-dependent mechanisms must contribute to control of virus replicatio n, and are of importance in determining the levels of virus subsequent ly persisting in the CNS, and hence the severity of the chronic demyel inating disease.