Organ-specific protective role of NKT cells in virus-induced inflammatory demyelination and myocarditis depends on mouse strain.

Theiler's murine encephalomyelitis virus (TMEV) can induce demyelination or myocarditis in susceptible mouse strains. A deficiency of NKT cells exacerbated TMEV-induced demyelinating disease (TMEV-IDD) in SJL/J and BALB/c mice. In C57BL/6 background, however, NKT-cell-deficient Jα18 KO mice remained as resistant to TMEV-IDD as wild-type mice. Echocardiography and histology showed that Jα18 KO mice developed more severe myocarditis (greater T cell infiltration and fibrosis) than wild-type mice, suggesting a protective role of NKT cells in myocarditis in C57BL/6 mice. Jα18 KO mice had higher cardiac viral RNA and anti-viral antibody titers, but had lower lymphoproliferation and IL-4 and IL-10 production.

Th17-biased RORγt transgenic mice become susceptible to a viral model for multiple sclerosis.

In a viral model for multiple sclerosis (MS), Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), both immune-mediated tissue damage (immunopathology) and virus persistence have been shown to cause pathology. T helper (Th) 17 cells are a Th cell subset, whose differentiation requires the transcription factor retinoic acid-related orphan receptor (ROR) γt, secrete pro-inflammatory cytokines, including IL-17, and can antagonize Th1 cells. Although Th17 cells have been shown to play a pathogenic role in immune-mediated diseases or a protective role in bacterial and fungal infections, their role in viral infections is unclear. Using newly established Th17-biased RORγt Tg mice, we tested whether Th17 cells could play a pathogenic or protective role in TMEV-IDD by contributing to immunopathology and/or by modulating anti-viral Th1 immune responses. While TMEV-infected wild-type littermate C57BL/6 mice are resistant to TMEV-IDD, RORγt Tg mice developed inflammatory demyelinating lesions with virus persistence in the spinal cord. TMEV-infected RORγt Tg mice had higher levels of IL-17, lower levels of interferon-γ, and fewer CD8(+) T cells, without alteration in overall levels of anti-viral lymphoproliferative and antibody responses, compared with TMEV-infected wild-type mice. This suggests that a Th17-biased "gain-of-function" mutation could increase susceptibility to virus-mediated demyelinating diseases.

Regulation of an autoimmune model for multiple sclerosis in Th2-biased GATA3 transgenic mice.

T helper (Th)2 cells have been proposed to play a neuroprotective role in multiple sclerosis (MS). This is mainly based on "loss-of-function" studies in an animal model for MS, experimental autoimmune encephalomyelitis (EAE), using blocking antibodies against Th2 related cytokines, and knockout mice lacking Th2-related molecules. We tested whether an increase of Th2 responses ("gain-of-function" approach) could alter EAE, the approach of novel GATA binding protein 3 (GATA3)-transgenic (tg) mice that overexpress GATA3, a transcription factor required for Th2 differentiation. In EAE induced with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, GATA3-tg mice had a significantly delayed onset of disease and a less severe maximum clinical score, compared with wild-type C57BL/6 mice. Histologically, GATA3-tg mice had decreased levels of meningitis and demyelination in the spinal cord, and anti-inflammatory cytokine profiles immunologically, however both groups developed similar levels of MOG-specific lymphoproliferative responses. During the early stage, we detected higher levels of interleukin (IL)-4 and IL-10, with MOG and mitogen stimulation of regional lymph node cells in GATA3-tg mice. During the late stage, only mitogen stimulation induced higher IL-4 and lower interferon-γ and IL-17 production in GATA3-tg mice. These results suggest that a preexisting bias toward a Th2 immune response may reduce the severity of inflammatory demyelinating diseases, including MS.