Activation-induced nonresponsiveness: A Th-dependent regulatory chekpoint in the CTL response

Ee Loon Tham, Protul Shrikant, Matthew F. Mescher

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

CD8 T cells undergo autocrine IL-2-dependent proliferation upon TCR engagement and costimulation, but within 3-4 days, they become activation-induced nonresponsive (AINR) and display a split anergy. They can lyse targets and secrete IFN-γ but they cannot produce IL-2 in response to TCR ligation and costimulation, due at least in part to an inability to up-regulate mitogen-activated protein kinases and IL-2 mRNA. Exogenous IL-2 can drive continued proliferation of AINR cells and nonresponsiveness is reversed within 1-2 days so that Ag-driven proliferation can resume. Mitogen-activated protein kinases and IL-2 mRNA can again be up-regulated, but "rewiring" has occurred so that these events no longer depend upon costimulation; TCR engagement is sufficient. Development of AINR appears to be a normal part of the differentiation program of CD8 T cells, providing a regulatory checkpoint to convert the initial helper-independent response to one that depends upon CD4 T cell help for continued expansion of the effector CTL. Once permission is given, in the form of IL-2, to pass this checkpoint, the CTL can make a prolonged response to persisting Ag in the absence of further CD4 T cell help.

Original languageEnglish (US)
Pages (from-to)1190-1197
Number of pages8
JournalJournal of Immunology
Volume168
Issue number3
StatePublished - Feb 1 2002
Externally publishedYes

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Interleukin-2
T-Lymphocytes
Mitogen-Activated Protein Kinase 1
Messenger RNA
Ligation
Up-Regulation

ASJC Scopus subject areas

  • Immunology

Cite this

Activation-induced nonresponsiveness : A Th-dependent regulatory chekpoint in the CTL response. / Tham, Ee Loon; Shrikant, Protul; Mescher, Matthew F.

In: Journal of Immunology, Vol. 168, No. 3, 01.02.2002, p. 1190-1197.

Research output: Contribution to journalArticle

Tham, EL, Shrikant, P & Mescher, MF 2002, 'Activation-induced nonresponsiveness: A Th-dependent regulatory chekpoint in the CTL response', Journal of Immunology, vol. 168, no. 3, pp. 1190-1197.
Tham, Ee Loon ; Shrikant, Protul ; Mescher, Matthew F. / Activation-induced nonresponsiveness : A Th-dependent regulatory chekpoint in the CTL response. In: Journal of Immunology. 2002 ; Vol. 168, No. 3. pp. 1190-1197.
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