A caspase-independent pathway of MHC class II antigen-mediated apoptosis of human B lymphocytes.
MHC class II molecules have a crucial role in thymic selection and in generating Ag-specific T cell responses. There is extensive evidence for second messenger generation via MHC class II molecules, which can lead to apoptosis of B lymphocytes. We have examined HLA class II-mediated apoptosis in both normal and tumoral human B lymphocytes. Phosphatidylserine exposure and DNA fragmentation were observed in B cells within 24 h of stimulation via HLA class II. In marked comparison with Fas, the cell-permeable and irreversible caspase inhibitors zVAD-fmk and DEVD-fmk failed to inhibit HLA-DR-mediated apoptosis. No direct activation of caspase 3 was detected, and cleavage of pro-caspase 3 was not observed. Cleavage of poly(ADP-ribose) polymerase was detected via Fas but not via HLA class II. Although phosphatidylinositol-3-kinase has been implicated in HLA class I-mediated apoptosis, neither wortmannin nor LY294002 affected HLA class II-mediated apoptosis. CD95-sensitive cells were used to reveal that death occurred independently of CD95-CD95 ligand interactions. Overall, these data reveal a pathway of HLA-DR-mediated apoptosis that neither requires nor involves caspases. Moreover, it is phosphatidylinositol-3-kinase independent and Fas/CD95 independent. This pathway of HLA class II-mediated apoptosis could have an important role in the regulation of APC populations or in the control of malignant B lymphocyte proliferations.
Drénou
B
B
Laboratoire d'Immunogénétique humaine, Institut National de la Santé et de la Recherche Médicale, U396, Hôpital Saint-Louis, Paris, France.
Blancheteau
V
V
Burgess
D H
DH
Fauchet
R
R
Charron
D J
DJ
Mooney
N A
NA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation / Q000276:immunology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000276:immunology; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D006868:Hydrolysis; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D015853:Cysteine Proteinase Inhibitors; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D009842:Oligopeptides; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D019014:fas Receptor; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases