TY - JOUR
T1 - The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance
AU - Eagar, Todd N.
AU - Karandikar, Nitin J.
AU - Bluestone, Jeffrey A.
AU - Miller, Stephen D.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
KW - Anergy
KW - Costimulation
KW - Experimental autoimmuune encephalomyelitis
KW - Proteolipid protein
KW - Tolerance
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U2 - 10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M
DO - 10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M
M3 - Article
C2 - 11920563
AN - SCOPUS:0036232603
SN - 0014-2980
VL - 32
SP - 972
EP - 981
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 4
ER -