HLA class II signaling mediates cellular activation and programmed cell death.
The class II human leucocyte antigens (HLA class II) are principally peptide presentation molecules. Signal transduction by these molecules has also been shown to transmit activation signals in both B and T lymphocytes by a pathway including protein tyrosine kinase activation, an intracellular calcium flux, and both the activation and transcriptional regulation of protein kinase C (PKC) isoforms. Apoptosis can also result from human leukocyte antigen class II stimulation. Inhibitors of gene transcription were used to inhibit activation and, therefore, to distinguish the signal transduction pathways important for apoptosis. This approach provided evidence that cellular activation and apoptosis undertook separate signaling pathways, and that PKC and intracellular calcium were shared between the two pathways, while tyrosine kinase activity was essential for cell activation. Further studies using cord blood B cells showed that these cells were incapable of generating a calcium flux after HLA class II ligation and were not subject to cell death. The importance of sustained levels of calcium for programmed cell death (PCD) was underlined since the restoration of a calcium flux enabled PCD of cord blood B cells via HLA class II. These results demonstrate that HLA class II stimulation initiates two distinct signal transduction pathways.
INSERM U396-Human Immunogenetics, Institut Biomédical des Cordeliers, Paris, France.
J P
JP
Truman
F
F
Garban
C
C
Choqueux
D
D
Charron
N
N
Mooney
D000328:Adult; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology; D002118:Calcium / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D017690:Cell Transplantation / Q000502:physiology; D002585:Cesarean Section; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005333:Fetus / Q000166:cytology; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D011247:Pregnancy; D011493:Protein Kinase C / Q000494:pharmacology; D015290:Second Messenger Systems; D013154:Spleen / Q000166:cytology
D000911:Antibodies, Monoclonal; D015220:Calcium Channels; D000949:Histocompatibility Antigens Class II; D003609:Dactinomycin; D011493:Protein Kinase C; D002118:Calcium