The lack of NF-kappa B transactivation and PKC epsilon expression in CD4(+)CD8(+) thymocytes correlates with negative selection.
Deletion of autoreactive thymocytes at the DP stage is the basis for tolerance to thymus-expressed self antigens. In this study we investigated whether distinct signalling pathways are induced in DP thymocytes as compared to mature T cells upon stimulation with antigen. Using triple transgenic mice expressing a TCR transgene, dominant negative ras/Mek proteins and a reporter gene construct with AP-1 or NF-kappa B binding sites, we showed a complete lack of transcriptional activity of NF-kappa B but not AP-1 in DP thymocytes, whereas both were transcriptionally active in mature T cells after antigenic stimulation. Lack of NF-kappa B induction correlated with increased death in response to antigen. AP-1 induction was dependent on the integrity of the ras/Mek pathway indicating that this pathway was activated in the DP thymocytes. In contrast, we found a complete lack of constitutive expression of the epsilon isoform of Protein Kinase C (PKC) in DP thymocytes, although it was present in mature thymocytes and peripheral T cells. Taken together the results suggest that the lack of PKC epsilon in DP thymocytes could lead to the absence of NF-kappa B activity after antigenic stimulation contributing to negative selection. Cell Death and Differentiation (2000) 7, 1253 - 1262.
Simon
A K
AK
Centre d'Immunologie INSERM-CNRS de Marseille Luminy, Marseille, France. katja.simon@ndm.ox.ac.uk
Auphan
N
N
Pophillat
M
M
Boyer
C
C
Ghosh
S
S
Rincón
M
M
Flavell
R A
RA
Schmitt-Verhulst
A M
AM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D006183:H-2 Antigens / Q000276:immunology / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology*; D018631:ras Proteins / Q000378:metabolism
D006183:H-2 Antigens; C078460:H-2K(sm1) antigen; D007527:Isoenzymes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon; D020930:MAP Kinase Kinase Kinases; D018631:ras Proteins