Activation-induced nonresponsiveness: a Th-dependent regulatory checkpoint in the CTL response.
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.
Tham
Ee Loon
EL
Center for Immunology, Department of Biochemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Shrikant
Protul
P
Mescher
Matthew F
MF
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D019898:Autocrine Communication / Q000276:immunology; D002460:Cell Line; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000201:enzymology / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D020928:Mitogen-Activated Protein Kinases