Pathogenesis and Immunoregulation of T Cell-Mediated CNS Autoimmune and Virus Diseases Our laboratory investigates the cellular and molecular mechanisms of the immunopathogenesis and specific immunoregulation of T cell-mediated autoimmune responses employing two mouse models of multiple sclerosis (MS) – Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (a virus-induced model of MS) and Relapsing Experimental Autoimmune Encephalomyelitis (R-EAE) (an autoimmune model of MS). Specific projects include: *Cellular and Molecular Mechanisms of T Cell Tolerance: Transgenic and molecular approaches are used to study the cellular and molecular mechanisms of T cell tolerance in CD4+ Th1 and Th2 subsets induced by peptide-pulsed, chemically-fixed antigen presenting cells and T cell receptor activation with non-mitogenic anti-CD3 *Immunopathology of TMEV-Induced Demyelinating Disease: MS is a T cell-mediated autoimmune demyelinating disease thought to be initiated by a virus infection. TMEV is a picornavirus which induces a chronic, CD4+ T cell-mediated demyelinating disease which models chronic-progressive MS. Myelin destruction is initiated by virus-specific CD4+ T cells targeting virus which chronically persists in the CNS. Autoimmune responses to myelin epitopes arise 3-4 weeks after onset of clinical disease in response to myelin damage by a process termed epitope spreading and play a major pathologic role in disease progression. The lab is currently elucidating how epitope spreading leads to autoimmune responses and has recently developed a molecular mimicry model wherein autoimmunity is induced by infection with a non-pathogenic variant of TMEV engineered to express molecular mimics of self myelin epitopes. *Immunopathology of Murine R-EAE: Following immunization with myelin peptides, SJL/J mice develop a CD4+ T cell-mediated demyelinating disease characterized by a relapsing-remitting clinical course. We have shown that relapses in this disease model are mediated by T cells primed to endogenous myelin antigens released during acute tissue destruction, a process termed epitope spreading. We are studying the mechanisms and anatomic location where T cells specific for these endogenous myelin epitopes are activated. The laboratory also uses this model to study the molecular mechanisms of pathogenesis and intrinsic regulation of this Th1-mediated autoimmune disease and to study the efficacy and cellular and molecular mechanisms operative in various immunoregulatory strategies (e.g., peptide-specific tolerance, suppression by CD4+CD25+ T regulatory cells, blockade of the B7/CD28 and CD40/CD154 costimulatory pathways, and blockade of homing molecules required by T cells to traffic to the CNS) that we have shown to be successful in treating pre-established disease. It is hoped that these strategies will eventually be employed as potential therapies for human autoimmune diseases including multiple sclerosis. *Innate and Adaptive Immune Functions of Glia Cells: Various approaches are used to study the ability of microglia and astrocytes to respond to infections via innate immune responses triggered by type I interferons and via signaling through Toll-like receptors. The ability of glial cell populations to process and present antigenic epitopes to virus-specific and autoreactive T cells is also being evaluated.