Reversible regulatory T cell-mediated suppression of myelin basic protein-specific T cells

Multiple Sclerosis (MS) is believed to be an autoimmune disease in which demyelination is mediated by T cells that recognize self antigens in the myelin sheath. To study mechanisms of tolerance to myelin, we utilized mice that express a transgenic T cell receptor specific for amino acids 121-140 of myelin basic protein (MBP), the principal epitope recognized in MBP-/- mice. When naive MBP121-140-specific transgenic T cells are transferred into T cell-deficient MBP+/+ mice, recipients develop a severe disease characterized by inflammation of the peripheral and central nervous systems. Immune competent recipients show no signs of autoimmunity. Reconstitution of T cell-deficient mice with CD3+ splenocytes prevents disease but regulatory activity is completely lost upon depletion of CD4+ or CD25+ cells, indicating a role for CD4+CD25 + cells in inhibiting disease.; In wild-type recipients, disease is prevented through suppression of Th1 cytokine production by the MBP121-140-specific T cells. Suppression is dependent on either IL-10 or TGF-beta activity. Administering reagents that activate antigen presenting cells (APCs) shortly after transfer of transgenic cells into wild-type mice abrogates protection and restores inflammatory cytokine production by the transgenic T cells. Administering the same reagents thirty days after transfer has the opposite effect and does not induce disease. Transfer of a second wave of transgenic cells into long-term recipients did not restore susceptibility of long-term recipients to disease induced by APC activation. Inhibition of the agonist-induced pathogenicity of this second wave of MBP-specific T cells depended on factors within the day 30 recipients and could not be transferred to wild-type mice that had not previously suppressed MBP-targeted autoimmunity by the Day 30 tolerized transgenic T cells alone. Despite the deeper state of tolerance reached after thirty days in wild-type mice, tolerized transgenic T cells regained their pathogenicity upon retransfer to T cell-deficient recipients. We have thus described an interplay between regulatory T cell-mediated and adaptive tolerance mechanisms wherein suppression of the initial pathogenicity of naive MBP-specific T cells by regulatory T cells allows development of a deeper state of tolerance to MBP in which activated APCs cannot induce disease but regulatory T cells are still required.