MHC Class II-mediated apoptosis by a nonpolymorphic MHC Class II peptide proceeds by activation of protein kinase C.
It was demonstrated previously that a peptide derived from a conserved region of MHC class II, HLA-DQA1, inhibits proliferation of allogeneic T cells in vitro. Administration of HLA-DQA1 in conjunction with allogeneic cells at the time of priming or at the time of rechallenge prevented the development of the delayed type hypersensitivity response in vivo. The immunomodulatory effects of HLA-DQA1 were associated with the induction of apoptosis in B cells, macrophages, and dendritic cells via a caspase-independent pathway. This study investigated the binding site and mechanism that mediates cell death induced by HLA-DQA1. It was demonstrated that HLA-DQA1 binds to MHC class II on the cell surface, causing MHC class II signaling, initiation of protein kinase C signaling, and mitochondrial membrane depolarization with resultant apoptosis. The data indicate that HLA-DQA1 binds to MHC class II outside the groove, in a manner similar to superantigen. These results suggest that HLA-DQA1 is a novel immunotherapy that may provide an effective means of targeting professional antigen-presenting cells, in particular B cells.
Zang
Weiping
W
Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Kalache
Safa
S
Lin
Marvin
M
Schroppel
Bernd
B
Murphy
Barbara
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005802:Genes, MHC Class II / Q000187:drug effects* / Q000502:physiology; D006683:HLA-DQ Antigens / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000502:physiology; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction
D006683:HLA-DQ Antigens; D011493:Protein Kinase C