The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance

Todd N. Eagar, Nitin J. Karandikar, Jeffrey A. Bluestone, Stephen D. Miller

Research output: Contribution to journalArticlepeer-review

100 Scopus citations


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-4lg 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.

Original languageEnglish (US)
Pages (from-to)972-981
Number of pages10
JournalEuropean Journal of Immunology
Issue number4
StatePublished - 2002


  • Anergy
  • Costimulation
  • Experimental autoimmuune encephalomyelitis
  • Proteolipid protein
  • Tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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