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The Journal of Immunology, 2002, 168: 1190-1197.
Copyright © 2002 by The American Association of Immunologists

Activation-Induced Nonresponsiveness: A Th-Dependent Regulatory Checkpoint in the CTL Response1

Ee Loon Tham*,{dagger}, Protul Shrikant2,*,{ddagger} and Matthew F. Mescher3,*,{ddagger}

* Center for Immunology, Departments of {dagger} Biochemistry, Molecular Biology, and Biophysics and {ddagger} Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

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-{gamma} 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.




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