The poststimulation program of CD4 versus CD8 T cells (death versus activation-induced nonresponsiveness).
Both CD8 and CD4 T cells undergo autocrine IL-2-induced proliferation and clonal expansion following stimulation with Ag and costimulation. The CD8 T cell response is transient because the cells rapidly become activation-induced nonresponsive (AINR) and exhibit split anergy. In these cells, the capacity for IL-2 production is lost, but TCR-mediated IFN-gamma production and cytotoxicity are maintained. At this point, the CTL become dependent on IL-2 provided by CD4 Th cells for continued expansion. If IL-2 is available to support expansion for a brief period, AINR is reversed and the cells regain the ability to produce IL-2. In this study, we show that CD4 T cells do not become AINR, but instead are rendered susceptible to Fas-mediated activation-induced cell death following stimulation through TCR and CD28. Using z-VAD-fmk or anti-Fas ligand mAb to inhibit cell death, we demonstrate that previously activated CD4 T cells retain the ability to up-regulate c-Jun N-terminal kinase activity and IL-2 mRNA levels upon TCR engagement and no longer require costimulation. This rewiring of signaling pathways is similar to that seen following reversal of AINR in CD8 T cells. Thus, CD8 and CD4 T cells appear to use distinct mechanisms, AINR and activation-induced cell death, respectively, to limit excessive clonal expansion following a productive response, while permitting important effector functions to be expressed.
Tham
Ee Loon
EL
Center for Immunology, Department of Biochemistry, University of Minnesota, Minneapolis, MN 55455, USA.
Mescher
Matthew F
MF
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D053222:Fas Ligand Protein; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone