MHC class II-mediated apoptosis of mature dendritic cells proceeds by activation of the protein kinase C-delta isoenzyme.
The mature dendritic cell (DC) is considered to be the most potent antigen-presenting cell. Regulation of the DC, particularly its survival, is therefore critical. Mature DC are markedly more sensitive to HLA-DR-mediated apoptosis than immature DC. To further characterize this key survival difference, we compared the intracellular signals initiated via HLA-DR in mature versus immature DC. Apoptosis was unchanged by inhibition of tyrosine kinases or phosphatases. HLA-DR-mediated re-localization of protein kinase C (PKC)-delta to the nucleus was detected in mature DC by confocal microscopy and by immunoblotting. Activation of PKC-delta in mature DC was revealed by the detection of the PKC-delta catalytic fragment in the nuclear fraction isolated from mature DC which had been stimulated via HLA-DR. The broad-spectrum PKC inhibitor, Calphostin C, as well as the PKC-delta-selective inhibitor, Rottlerin, inhibited HLA-DR-mediated apoptosis of mature cells. Taken together, these data reveal a role for the PKC-delta isoenzyme in regulating HLA class II-mediated apoptosis of mature DC. Thus, the lifespan of the mature DC could be controlled by signals generated in the course of antigen presentation, and thereby prevent DC persistence and prolonged stimulation of T and B lymphocytes.
Bertho
Nicolas
N
INSERM U396, Immunogenetique Humaine, Institut Biomedical des Cordeliers, 75006 Paris, France.
Blancheteau
Vincent M
VM
Setterblad
Niclas
N
Laupeze
Beatrice
B
Lord
Janet M
JM
Drénou
Bernard
B
Amiot
Laurence
L
Charron
Dominique J
DJ
Fauchet
Renée
R
Mooney
Nuala
N
D017951:Antigen Presentation; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D004791:Enzyme Inhibitors; D006684:HLA-DR Antigens; D009281:Naphthalenes; D011505:Protein-Tyrosine Kinases; C496628:PRKCA protein, human; C497258:PRKCD protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D017027:Protein Tyrosine Phosphatases; C058819:calphostin C