An important recently recognized barrier to induction of immunologic tolerance in humans is the fact that the adaptive immune response, by virtue of evolutionary design, is destined to generate immunologic memory;and initial data suggest that memory T cells tend to be resistant to induction of tolerance. EAE is an inflammatory disease of the central nervous system that mimics certain aspects of MS. We have established a new model of EAE that is mediated by antigen-specific memory T cells that is distinct from disease mediated by effector T cells. The major goal of this project is to investigate the role of memory T cells EAE, and to investigate their susceptibility to tolerance strategies in vivo. Aim1: We will investigate the characteristics of disease mediated by memory versus effector T cells, including clinical features, central nervous system (CNS) pathology, and peripheral immune responses. Aim 2: Our hypothesis is that autoreactive memory T cells can be activated by nonspecific immune stimuli (viral infection, inflammation, vaccination) leading to reactivation/progression of clinical disease. In this aim we will investigate which stimuli can activate autoreactive memory T cells in vivo and define the clinical and pathological disease pattern mediated by these cells and the mechanisms of how this happens. Aim 3: Our hypothesis is that autoreactive memory T cells are less dependent on conventional (CD28) T cell costimulatory pathways for activation and require distinct and unique T cell costimulatory signals for full activation, differentiation and survival in vivo. These cosimulatory pathways include ICOS-B7h and CD134-CD143L. Using blocking antibodies against B7h and CD134L, we will investigate the functions and mechanisms of these pathways in regulating autoimmune disease mediated by memory T cells in vivo.