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

Research output: Contribution to journalArticle

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

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
Volume32
Issue number4
DOIs
StatePublished - May 4 2002

PMID: 11920563

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The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. / Eagar, Todd N.; Karandikar, Nitin J.; Bluestone, Jeffrey A.; Miller, Stephen D.

In: European Journal of Immunology, Vol. 32, No. 4, 04.05.2002, p. 972-981.

Research output: Contribution to journalArticle

Harvard

Eagar, TN, Karandikar, NJ, Bluestone, JA & Miller, SD 2002, 'The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance' European Journal of Immunology, vol. 32, no. 4, pp. 972-981. https://doi.org/10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M

APA

Eagar, T. N., Karandikar, N. J., Bluestone, J. A., & Miller, S. D. (2002). The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. European Journal of Immunology, 32(4), 972-981. https://doi.org/10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M

Vancouver

Eagar TN, Karandikar NJ, Bluestone JA, Miller SD. The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. European Journal of Immunology. 2002 May 4;32(4):972-981. https://doi.org/10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M

Author

Eagar, Todd N. ; Karandikar, Nitin J. ; Bluestone, Jeffrey A. ; Miller, Stephen D. / The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance. In: European Journal of Immunology. 2002 ; Vol. 32, No. 4. pp. 972-981.

BibTeX

@article{5d4513d9c0bd4243a073d4ba483c1bba,
title = "The role of CTLA-4 in induction and maintenance of peripheral T cell tolerance",
abstract = "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.",
keywords = "Anergy, Costimulation, Experimental autoimmuune encephalomyelitis, Proteolipid protein, Tolerance",
author = "Eagar, {Todd N.} and Karandikar, {Nitin J.} and Bluestone, {Jeffrey A.} and Miller, {Stephen D.}",
year = "2002",
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doi = "10.1002/1521-4141(200204)32:4<972::AID-IMMU972>3.0.CO;2-M",
language = "English (US)",
volume = "32",
pages = "972--981",
journal = "European Journal of Immunology",
issn = "0014-2980",
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RIS

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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 - 2002/5/4

Y1 - 2002/5/4

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

VL - 32

SP - 972

EP - 981

JO - European Journal of Immunology

T2 - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

IS - 4

ER -

ID: 16791865