Pathway of apoptosis induced in Jurkat T lymphoblasts by anti-HLA class I antibodies.
We demonstrated recently that human leukocyte antigen (HLA) class I human monoclonal antibodies (mAbs) are able to induce apoptosis of resting human lymphocytes as well as Jurkat lymphoblastic T cells. We now analyzed the signaling pathway involved in apoptosis mediated by human HLA class I allele-specific mAb OK2F3 and mouse monomorphic mAb W6/32. An inhibitor of a broad spectrum of caspases had only a moderate inhibiting effect, and an inhibitor of caspase 3 failed to inhibit HLA class I-mediated apoptosis. Although caspase 3 activation was not observed, internucleosomal DNA fragmentation was found in half of the apoptotic cells. Importantly, the mitochondrio-nuclear redistribution of apoptosis inducing factor (AIF), a caspase-independent mitochondrial death effector, was detected after 1 hour of treatment with human anti-HLA mAb and was associated with large-scale DNA fragmentation, whereas the release of cytochrome c, which is responsible for caspase-dependent internucleosomal fragmentation, followed AIF translocation and occurred after 2 hours. Our results indicate that apoptosis mediated through HLA class I molecules represents a unique mechanism of cell death in Jurkat T lymphoblasts that involves two parallel pathways, one caspase-independent and the other caspase-dependent. This study clarifies the precise mechanism of anti-HLA antibody-induced apoptosis which might have clinical implications.
Daniel
Dinara
D
Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg, Heidelberg, Germany.
Opelz
Gerhard
G
Mulder
Arend
A
Kleist
Christian
C
Süsal
Caner
C
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006680:HLA Antigens / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D006680:HLA Antigens; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases