Antibody response is required for protection from Theiler's virus-induced encephalitis in C57BL/6 mice in the absence of CD8+ T cells

Abstract

Intracerebral infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease and this system serves as a relevant infectious model for human multiple sclerosis. It was previously shown that beta2M-deficient C57BL/6 mice lacking functional CD8+ T cells display increased viral persistence and enhanced susceptibility to TMEV-induced demyelination, and yet the majority of mice are free of clinical signs. To understand the mechanisms involved in this general resistance of C57BL/6 mice in the absence of CTL responses, mice (muMT) deficient in the B-cell compartment lacking membrane IgM molecules were treated with anti-CD8 antibody and then infected with TMEV. Although little difference in the proliferative responses of peripheral T cells to UV-inactivated TMEV and the resistance to demyelinating disease was observed between virus-infected muMT and control B6 mice, the levels of CD4(+) T cells were higher in the CNS of muMT mice. However, after treatment with anti-CD8 antibody, 100% of the mice displayed clinical gray matter disease and prolonged viral persistence in muMT mice, while only 10% of B6 mice showed clinical symptoms and very low viral persistence. Transfusion of sera from TMEV-infected B6 mice into anti-CD8 antibody-treated muMT mice partially restored resistance to virus-induced encephalitis. These results indicate that the early anti-viral antibody response is also important in the protection from TMEV-induced encephalitis particularly in the absence of CD8+ T cells.

Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice

“…The importance of CD8 ϩ T cells in viral resolution is consistent with previous reports of mice with resistant backgrounds (38,45,47). However, it is also possible that deficiencies in virus-specific CD4 ϩ T-cell and antibody responses in P1-Tg mice contribute to the lack of viral clearance, as these immune responses play a role in TMEV clearance from the CNS, especially during the early stages of viral infection (6,22,40,43). Surprisingly, however, TMEV-infected B6 P1-Tg mice with high levels of viral persistence developed neither symptomatic disease nor demyelinating lesions as late as 250 days pi (Fig.…”

“…Like the CD8 ϩ T cells, vigorous antiviral CD4 ϩ T-cell responses in the early stages of viral infection also are important in acquiring resistance to TMEV-IDD (40). Furthermore, virus-specific antibody responses are required to confer resistance to TMEV infection, especially in the absence of CD8 ϩ T cells (22). These data suggest that various virusspecific immune responses contribute to viral resolution and/or resistance to TMEV-IDD in B6 mice.…”

“…Despite numerous studies, the relationship between viral persistence and the pathogenesis of demyelinating disease remains unclear. The removal of either B or T cells from resistant mice results in elevated viral persistence but increased demyelination with/without marginal clinical symptoms or encephalitis, a different neurological disease often without demyelination (6,22,41,42,45,47). These results imply that demyelination and/or the development of demyelinating disease is tightly associated with viral persistence.…”

“…Although CD4 ϩ T-cell-mediated immune responses are considered pathogenic (16,57), virus-specific CD4 ϩ T cells also may provide protection by contributing to viral clearance and limiting viral replication during the early stages of viral infection (6,9). Virus-specific antibody responses also may contribute to protection, although again the protection is restricted during the early phase of infection (22,23,54). Taking these findings together, virusspecific humoral and cellular immune responses seem to contribute to controlling viral loads in susceptible SJL mice, depending upon the stage of viral infection.…”

“…It was previously shown that resistant B6 mice, in the absence of both CD8 ϩ T-cell and antibody responses, develop encephalitis rather than demyelination following infection with TMEV (22). Therefore, the presence of low but significant levels of anti-TMEV antibody responses in P1-Tg mice may have prevented the development of encephalitis.…”