ovalbumin and myelin-proteolipid-protein-(178-191)

T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.

Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Autoantigens; Autoimmune Diseases; B7-1 Antigen; B7-2 Antigen; Capsid; Capsid Proteins; Cells, Cultured; Clonal Anergy; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunoconjugates; Inflammation; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Mutant Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteolipid Protein; Ovalbumin; Peptide Fragments; Receptors, Antigen, T-Cell; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets; Thymectomy