Anti-human class I MHC antibodies induce apoptosis by a pathway that is distinct from the Fas antigen-mediated pathway.
5H7, an anti-human class I MHC mAb that recognizes a monomorphic determinant of the alpha3 domain, profoundly inhibits T lymphocyte activation. The present study was designed to determine the role of programmed cell death in 5H7-mediated immune suppression. Incubation of PBMC with 5H7 mAb induced a marked reduction in viable cell recovery (VCR) of T cells (<10% VCR), NK cells (<1% VCR), and B cells (<1% VCR). In addition, 5H7 inhibited proliferation and VCR of JY, DBS-521, and BevD tumor lines as well as cells transfected with HLA-B27. Morphologic changes characteristic of apoptosis were induced by 5H7, including cell membrane blebbing, cytoplasmic vacuolization, condensation of nuclear chromatin, and nuclear fragmentation. Furthermore, DNA fragmentation was demonstrated in 5H7-treated PBMC using a TdT-mediated end-labeling (TUNEL) technique. 5H7, but not anti-Fas mAb, induced apoptosis of cell lines derived from patients with Niemann-Pick disease that lack acidic sphingomyelinase activity. In addition, induction of cell death by 5H7 was not inhibited by IL-1beta-converting enzyme (ICE) inhibitors under conditions that fully suppressed Fas-mediated apoptosis. These findings suggest that signal transduction through "classical" human class I MHC molecules induces apoptosis by a Fas-independent pathway that does not require acidic sphingomyelinase, is independent of ICE protease, and may represent a unique pathway of cell death in human lymphocytes.
Woodle
E S
ES
Department of Surgery, University of Chicago Pritzker School of Medicine, IL 60637, USA.
Smith
D M
DM
Bluestone
J A
JA
Kirkman
W M
WM
Green
D R
DR
Skowronski
E W
EW
D000328:Adult; D017209:Apoptosis / Q000276:immunology*; D020170:Caspase 1; D016923:Cell Death / Q000276:immunology; D048429:Cell Size / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D053938:DNA Fragmentation / Q000276:immunology; D004789:Enzyme Activation; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007375:Interleukin-1 / Q000378:metabolism; D007518:Isoantibodies / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000276:immunology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D015395:Histocompatibility Antigens Class I; D007375:Interleukin-1; D007518:Isoantibodies; D019014:fas Receptor; D013108:Sphingomyelin Phosphodiesterase; D003546:Cysteine Endopeptidases; D020170:Caspase 1