Murine Cytomegalovirus Infection Induces Susceptibility to EAE in Resistant BALB/c Mice

Abstract

In contrast to C57BL/6 mice, BALB/c mice are relatively resistant to the induction of experimental autoimmune encephalomyelitis (EAE) after challenge with MOG35–55 peptide. Here, we provide the first evidence that infection with murine cytomegalovirus (MCMV) in adulthood abrogates this resistance. Infected BALB/c mice developed clinical and histological signs similar to those seen in susceptible C57BL/6 mice. In addition to CD4+ cells, large proportion of cells in the infiltrate of diseased BALB/c mice was CD8+, similar with findings in multiple sclerosis. CD8+ cells that responded to ex vivo restimulation with MOG35–55 were not specific for viral epitopes pp89 and m164. MCMV infection favors proinflammatory type of dendritic cells (CD86+CD40+CD11c+) in the peripheral lymph organs, M1 type of microglia in central nervous system, and increases development of Th1/Th17 encephalitogenic cells. This study indicates that MCMV may enhance autoimmune neuropathology and abrogate inherent resistance to EAE in mouse strain by enhancing proinflammatory phenotype of antigen-presenting cells, Th1/Th17, and CD8 response to MOG35–55.

Interleukin-17 in Chronic Inflammatory Neurological Diseases

“…No inflammatory T1 and T17 cells were found in the CNS of BALB/c mice immunized with MOG 35−55 (174), while in the CNS of unimmunized BALB/c mice infected with MCMV neonatally, Tc1 cells (IFN-γ and T-bet+) dominated (178). CD8+ T cells isolated from CNS of MCMV-infected and MOG 35−55 -immunized mice produced inflammatory cytokines in response to in vitro MOG 35−55 peptide stimulation but were not specific for viral epitopes pp89 and m164 (174). These findings indicate that the newly developing autoimmune process in MOG 35−55 -immunized BALB/c mice previously infected with MCMV attracts a new population of IL-17producing CD8+ cells that participate in the development of autoimmunity (177).…”

“…Brain infiltrates in MCMV-infected BALB/c mice were more significant that in C57BL/6 mice, with a similar number of CD4+ and CD8+ cells, contrary to the dominantly CD4+ cells in C57BL/6 mice, which develop "typical" EAE (105). The encephalitogenic potential of CD4+ T cells in the CNS infiltrates of BALB/c mice is further documented by the detection of CCR6, the key molecule that mediates the initial infiltration of the CNS by Th17 cells (174,175). Almost equal participation of IFN-γ-and Tbet (Th1)-and IL-17-and RORγt (Th17)-expressing cells was found in the CNS of MCMV-infected MOG 35−55 immunized BALB/c mice, in contrast to almost exclusive CNS infiltration with Th1 cells in C57BL/6 mice infected with γHV-68 before EAE induction (174,176).…”

“…In our previous studies, we have shown that overcoming resistance to induction of EAE with MOG 35−55 peptide of BALB/c mice by infection with murine cytomegalovirus (MCMV) (174) or by deletion of ST2 gene (169) is associated with increased production of IL-17 in T cells.…”

“…The encephalitogenic potential of CD4+ T cells in the CNS infiltrates of BALB/c mice is further documented by the detection of CCR6, the key molecule that mediates the initial infiltration of the CNS by Th17 cells (174,175). Almost equal participation of IFN-γ-and Tbet (Th1)-and IL-17-and RORγt (Th17)-expressing cells was found in the CNS of MCMV-infected MOG 35−55 immunized BALB/c mice, in contrast to almost exclusive CNS infiltration with Th1 cells in C57BL/6 mice infected with γHV-68 before EAE induction (174,176). Further, CNS infiltrates of BALB/c mice infected with MCMV before MOG 35−55 immunization contained CD8+ cells that express T1 and T17 transcriptional factors and corresponding cytokines, TNF-α and IFN-γ (Tc1) and IL-17 (Tc17 cells) (174).…”

“…Since cerebrospinal fluid of early-stage MS patients contains a greater number of Tc17 cells in comparison with peripheral blood, these cells are considered to be required for the accumulation of Th17 cells in the CNS in MS (177). No inflammatory T1 and T17 cells were found in the CNS of BALB/c mice immunized with MOG 35−55 (174), while in the CNS of unimmunized BALB/c mice infected with MCMV neonatally, Tc1 cells (IFN-γ and T-bet+) dominated (178). CD8+ T cells isolated from CNS of MCMV-infected and MOG 35−55 -immunized mice produced inflammatory cytokines in response to in vitro MOG 35−55 peptide stimulation but were not specific for viral epitopes pp89 and m164 (174).…”