Abstract
The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) induces a T cell-mediated demyelinating disease. This system has been studied as a relevant infection model for multiple sclerosis (MS). Therefore, defining the type of T cell responses and their functions is critically important for understanding the relevant pathogenic mechanisms. In this study, we adoptively transferred naive VP2-specific TCR-Tg CD4+ T cells into syngeneic susceptible SJL mice and monitored the development of the disease and the activation and proliferation of CD4+ T cells during the early stages of viral infection. The preexisting VP2-specific naive CD4+ T cells promoted the pathogenesis of the disease in a dose-dependent manner. The transferred VP2-specific CD4+ T cells proliferated rapidly in the CNS starting at 2–3 dpi. High levels of FoxP3+CD4+ T cells were found in the CNS early in viral infection (3 dpi) and persisted throughout the infection. Activated VP2-specific FoxP3+CD4+ T cells inhibited the production of IFN-γ, but not IL-17, via the same VP2-specific CD4+ T cells without interfering in proliferation. Thus, the early presence of regulatory T cells in the CNS with viral infection may favor the induction of pathogenic Th17 cells over protective Th1 cells in susceptible mice, thereby establishing the pathogenesis of virus-induced demyelinating disease.
Highlights
The infection with Theiler’s murine encephalomyelitis virus (TMEV) results in viral persistence in the CNS of susceptible mice and induces demyelinating disease similar to multiple sclerosis [1,2]
The type of CD4+ T cell responses preferentially contribute to the pathogenesis of viral demyelinating disease, i.e., IFN-γ producing Th1 cells protect against the pathogenesis [12], and IL-17 producing Th17 cells promote the pathogenesis by interfering with the apoptosis of virus-infected cells and the cytolysis of target cells by CD8+ T cells [13]
Our results demonstrate that preexisting naive VP2-specific CD4+ T cells promote the pathogenesis of TMEV-induced demyelinating disease at high initial viral loads, but VP2-primed VP2-specific CD4+ T cells protect against the pathogenesis
Summary
The infection with Theiler’s murine encephalomyelitis virus (TMEV) results in viral persistence in the CNS of susceptible mice and induces demyelinating disease similar to multiple sclerosis [1,2]. This system has been extensively used as a relevant infection model for multiple sclerosis. Higher levels of FoxP3+CD4+T cells, which regulate the virus-specific Th1 and CD8+ T cells, were found in the CNS and periphery of TMEV-infected susceptible SJL mice compared to those in infected resistant B6 mice [14]. It is unknown whether such regulatory T cells inhibit the production of a specific cytokine activated with viral determinants or how pathogenic Th17 cells are amplified after TMEV infection
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