CD40L is critical for protection from demyelinating disease and development of spontaneous remyelination in a mouse model of multiple sclerosis

Theiler's murine encephalomyelitis virus (TMEV) induces acute neuronal dise ase followed by chronic demyelination in susceptible strains of mice. In th is study we examined the role of a limited immune defect (deletion or block ing of CD40 ligand [CD40L]) on the extent of brain disease, susceptibility to demyelination, and the ability of demyelinated mice to spontaneously rem yelinate following TMEV infection. We demonstrated that CD40L-dependent imm une responses participate in pathogenesis in the cerebellum and the spinal cord white matter but protect the striatum of susceptible SJL/J mice. In mi ce on a background resistant to TMEV-induced demyelination (C57BL/6), the l ack of CD40L resulted in increased striatal disease and meningeal inflammat ion. In addition, CD40L was required to maintain resistance to demyelinatio n and clinical deficits in H-2(b) mice. CD40L-mediated interactions were al so necessary for development of protective H-2(b)-restricted cytotoxic T ce ll responses directed against the VP2 region of TMEV as well as for spontan eous remyelination of the spinal cord white matter. The data presented here demonstrated the critical role of this molecule in both antibody- and cell -mediated protective immune responses in distinct phases of TMEV-mediated p athology.