HLA class II signals sensitize B lymphocytes to apoptosis via Fas/CD95 by increasing FADD recruitment to activated Fas and activation of caspases.
Human leukocyte antigen (HLA) class II heterodimers have a well defined role in peptide presentation to helper T lymphocytes. Moreover, engagement of HLA class II molecules leads to signal transduction in the antigen presenting cell. Signaling via HLA-DR increases CD95 mediated hypoploidy in B-cell blasts. Given the importance of CD95 for the homeostasis of lymphocyte populations, we examined the impact of the HLA-DR signal on the most proximal events in the CD95 apoptotic pathway. CD95 activation recruits the adapter molecule Fas-associated death domain protein (FADD) and thereby provides a scaffold for procaspase-8 activation. The HLA-DR signal increased both recruitment of FADD and activation of caspases-3 and -8 via CD95 activation. Sensitization was tightly controlled because neither FADD recruitment to CD95 nor caspase activation was induced via HLA-DR alone. In contrast, the HLA-DR signal and the CD95 signal both led to decreased mitochondrial membrane potential. Taken together, these data indicate that ligand interaction with HLA class II molecules preactivates the antigen presenting cell for death in the event of a subsequent interaction with the CD95 ligand. This would ensure termination of a specific immune response, particularly in cells with limited sensitivity to CD95 mediated apoptosis alone.
Blancheteau
Vincent
V
INSERM U396, Immunogénétique Humaine, Institut Biomédical des Cordeliers, Paris, France.
Charron
Dominique
D
Mooney
Nuala
N
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D004789:Enzyme Activation; D000939:Epitopes / Q000276:immunology; D053200:Fas-Associated Death Domain Protein; D005434:Flow Cytometry; D005802:Genes, MHC Class II; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology; D011003:Ploidies; D021381:Protein Transport; D015398:Signal Transduction; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D000939:Epitopes; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D000949:Histocompatibility Antigens Class II; D019014:fas Receptor; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases