Rapid Expansion of Virus-Specific CD4⁺ T Cell Types in the CNS of Susceptible Mice Infected with Theiler's Virus

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.