The role of cellular immune response in Theiler's virus-induced central nervous system demyelination

Abstract Theiler's murine encephalomyelitis virus (TMEV) persists in spinal cord white matter of susceptible mice (e.g., SJL/J), resulting in chronic inflammation and demyelination. Reconstitution of severe combined immunodeficient (SCID) mice with CD4 + T- or CD8 + T-lymphocytes results in extensive TMEV-induced demyelination, and depletion of CD8 + T-lymphocytes in the early or late phase of the disease decreases the extent of demyelination, indicating that the cellular immune response against the virus plays a key role in myelin destruction. In susceptible mice, the demyelinated lesions are characterized by infiltration of a large numbers of B- and T-lymphocytes; whereas in mice resistant to TMEV-induced demyelination (e.g., C57BL/6), virus clearance requires infiltration of between 2.9×10 5 and 5.7×10 5 CD8 + T-lymphocytes and between 3.4×10 5 and 6.1×10 5 CD4 + T-lymphocytes per mouse in the brain 5–9 days post infection. Transgenic expression of capsid proteins of TMEV abrogates resistance in C56BL/6 mice, rendering the mice susceptible to TMEV persistence and demyelination. Comparison of the kinetics of virus replication and B- and T-lymphocyte infiltration in mice lacking key adhesion molecules ( l -selectin ( l -sel −/− ), P-selectin (P-sel −/− ), intracellular adhesion molecule-1 (ICAM-1 −/− ), or leukocyte function-associated antigen-1 (LFA-1 −/− )) demonstrates a role for individual adhesion molecules in recruitment of immune cells into central nervous system (CNS), but the role is not significant to prevent eventual virus clearance.