title: CD8+ T cells become nonresponsive (anergic) following activation in the presence of costimulation.
abstract: CD8+ T cells stimulated in vitro with anti-TCR mAb and B7-1 or ICAM-1 produce IL-2 and clonally expand. Effector function is acquired within 3 days, but proliferation ceases and the cells begin to die by apoptosis. Stimulation in vivo with B7-1-expressing allogeneic tumor results in the same sequence of events with a comparable time course. In both cases, the cells become anergic within 3 or 4 days of responding; they can no longer respond by producing IL-2 and proliferating, but can still be stimulated to proliferate in response to exogenous IL-2. This activation-induced nonresponsiveness (AINR) is not simply a consequence of ongoing cell death; cytokines that promote survival (IL-7 or IFN-alpha) or proliferation (human IL-2) do not restore the ability to produce IL-2 in response to costimulation. Although similar to the anergy described for CD4+ T cell clones, AINR differs in that it results from an initial stimulation with both signal 1 and signal 2. AINR appears to be an aspect of the normal differentiation of fully stimulated CD8+ T cells. It is probably important in regulating CTL responses; it limits the initial T helper-independent response and converts it to a response that requires T cell help to be sustained and further expanded. When the initial helper-independent response is not sufficient to clear Ag, and if help is not available, AINR likely results in tolerance to the Ag.
authors.affiliation: Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Deeths
authors.forename: R M
authors.initials: RM
authors.lastname: Kedl
authors.forename: M F
authors.initials: MF
authors.lastname: Mescher
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000502:physiology; D018122:B7-1 Antigen / Q000378:metabolism / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D016923:Cell Death / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D002999:Clone Cells; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008863:Microspheres; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018799:Intercellular Adhesion Molecule-1; D000069594:Abatacept