Regulation of activator protein-1 and NF-kappa B in CD8+ T cells exposed to peripheral self-antigens.
The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown. In this study, we analyzed the regulation of AP-1- and NF-kappa B-mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes. Naive CD8(+)Désiré (Des)(+) T cells isolated from the Des TCR-transgenic mice that are specific for the H-2K(b) class I Ag were transferred into Alb-K(b)-transgenic mice that express the H-2K(b) Ag on hepatocytes only. Tolerance develops in these mice. We found that the self-reactive CD8(+)Des(+) T cells were transiently activated, then became unresponsive and were further deleted. In contrast to CD8(+)Des(+) T cells activated in vivo with APCs, which express high AP-1 and high NF-kappa B transcriptional activity, the unresponsive CD8(+)Des(+) T cells expressed no AP-1 and only weak NF-kappa B transcriptional activity. The differences in NF-kappa B transcriptional activity correlated with the generation of distinct NF-kappa B complexes. Indeed, in vivo primed T cells predominantly express p50/p50 and p65/p50 dimers, whereas these p50-containing complexes are barely detectable in tolerant T cells that express p65- and c-Rel-containing complexes. These observations suggest that fine regulation of NF-kappa B complex formation may determine T cell fate.
Centre d'Immunologie de Marseille-Luminy, Institut National de la Santé et de la Recherche Médicale/Centre National de la Recherche Scientifique/Université de la Méditerranée, Marseille, France. guerder@ciml.univ-mrs.fr
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D019264:Adoptive Transfer; D000418:Albumins / Q000235:genetics; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D002469:Cell Separation; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics; D007116:Immunization, Passive; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051020:bcl-X Protein
D000418:Albumins; D001324:Autoantigens; C494812:Bcl2l1 protein, mouse; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D051020:bcl-X Protein