Differential requirements for NF-kappaB and AP-1 trans-activation in response to minimal TCR engagement by a partial agonist in naive CD8 T cells.
We investigated the basis for partial reactivity of naive CD8 T cells expressing an alloreactive transgenic TCR in response to a mutant alloantigen. When unstimulated APCs were used, IFN-gamma as well as IL-2 and cell proliferation were observed in response to wild-type Ag, whereas mutant Ag induced only IFN-gamma. DNA binding and reporter gene assays showed that the response to mutant Ag involved NF-kappaB, but not AP-1 activation, whereas wild-type Ag activated both transcription factors. Increasing the contribution of costimulatory signals by using LPS-activated APCs partially corrected the activation by mutant Ag, because proliferation and weak IL-2 production could be measured. This also led to AP-1 activation, albeit with delayed kinetics, in response to mutant Ag. To explain how engagement of the same TCR by distinct ligands results in different T cell responses, it may be proposed, in line with models stressing the importance of the kinetics of Ag/TCR interaction, that two types of signals be distinguished: a "fast" short-lived signal is sufficient to activate NF-kappaB; whereas a "slow" signal obtained after prolonged TCR engagement is required for AP-1 activation. Failure to activate AP-1 in limiting conditions (unstimulated mutant APC) was partially corrected by increasing costimulation.
Auphan
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N
Centre d'Immunologie, Institut National de la Santé et de la Recherche Médicale-Centre National de la Recherche Scientifique (INSERM-CNRS) de Marseille-Luminy, France. auphan@ciml.univ-mrs.fr
Ghosh
S
S
Flavell
R A
RA
Schmitt-Verhulst
A M
AM
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001665:Binding Sites / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006183:H-2 Antigens / Q000096:biosynthesis / Q000502:physiology*; D007399:Interphase / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology*; D019076:Transgenes / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D004247:DNA