Signaling alterations in activation-induced nonresponsive CD8 T cells.
Costimulation-dependent production and autocrine use of IL-2 by activated CD8 T cells results in initial clonal expansion, but this is transient. The cells quickly become anergic, unable to produce IL-2 in response to Ag and costimulation, irrespective of the form of costimulation. This activation-induced non-responsiveness (AINR) differs from "classical" anergy in that it results despite the cells receiving both signal 1 and signal 2. AINR cells can still proliferate in response to exogenous IL-2, but can no longer produce it. Other TCR-mediated events including cytolytic function and IFN-gamma production are not affected in the AINR state. To characterize the mechanism(s) responsible for lack of IL-2 production in CD8 T cells in the AINR state, microspheres bearing immobilized anti-TCR Abs or peptide-MHC complexes, B7-1, and ICAM-1 were used to provide well-defined stimuli to the cells. Comparison of normal and AINR cells revealed that in AINR cells extracellular signal-regulated kinase (ERK) is upregulated more transiently, Janus kinase activation is substantially reduced, and activation of p38 is eliminated. PMA and ionomycin restored proliferation and IL-2 production in AINR cells, indicating a signaling defect upstream of Ras and protein kinase C. Inhibitors of ERK (PD98059) and of p38 kinase (SB202190) blocked IL-2 mRNA expression and proliferation of both peptide-MHC/B7-1/ICAM-1-stimulated normal cells and PMA/ionomycin-stimulated AINR cells. Together these results demonstrate that activation of at least ERK and p38 is essential for IL-2 production by CD8 T cells and that up-regulation of these mitogen-activated protein kinases, along with Janus kinase, is defective in AINR cells.
Tham
E L
EL
Center for Immunology, Department of Biochemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Mescher
M F
MF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics; D004789:Enzyme Activation / Q000276:immunology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008863:Microspheres; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D018122:B7-1 Antigen; D007376:Interleukin-2; D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D015759:Ionomycin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate