CD47 signals T cell death.
Activation-induced death of T cells regulates immune responses and is considered to involve apoptosis induced by ligation of Fas and TNF receptors. The role of other receptors in signaling T cell death is less clear. In this study we demonstrate that activation of specific epitopes on the Ig variable domain of CD47 rapidly induces apoptosis of T cells. A new mAb, Ad22, to this site induces apoptosis of Jurkat cells and CD3epsilon-stimulated PBMC, as determined by morphological changes, phosphatidylserine exposure on the cell surface, uptake of propidium iodide, and true counts by flow cytometry. In contrast, apoptosis was not observed following culture with anti-CD47 mAbs 2D3 or B6H12 directed to a distant or closely adjacent region, respectively. CD47-mediated cell death was independent of CD3, CD4, CD45, or p56lck involvement as demonstrated by studies with variant Jurkat cell lines deficient in these signaling pathways. However, coligation of CD3epsilon and CD47 enhanced phosphatidylserine externalization on Jurkat cells with functional CD3. Furthermore, normal T cells required preactivation to respond with CD47-induced apoptosis. CD47-mediated cell death appeared to proceed independent of Fas or TNF receptor signaling and did not involve characteristic DNA fragmentation or requirement for IL-1beta-converting enzyme-like proteases or CPP32. Taken together, our data demonstrate that under appropriate conditions, CD47 activation results in very rapid T cell death, apparently mediated by a novel apoptotic pathway. Thus, CD47 may be critically involved in controlling the fate of activated T cells.
Pettersen
R D
RD
Department of Pediatric Research, The National Hospital, Oslo, Norway. rolf.pettersen@klinmed.uio.no
Hestdal
K
K
Olafsen
M K
MK
Lie
S O
SO
Lindberg
F P
FP
D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000276:immunology; D017252:CD3 Complex / Q000502:physiology; D015704:CD4 Antigens / Q000502:physiology; D051928:CD47 Antigen; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D003599:Cytoskeleton / Q000276:immunology / Q000502:physiology; D004792:Enzyme Precursors / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000378:metabolism; D007399:Interphase / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000502:physiology; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000502:physiology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D017252:CD3 Complex; D015704:CD4 Antigens; D051928:CD47 Antigen; C497894:CD47 protein, human; D002352:Carrier Proteins; D004792:Enzyme Precursors; D018984:Epitopes, T-Lymphocyte; D007135:Immunoglobulin Variable Region; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018124:Receptors, Tumor Necrosis Factor; D019014:fas Receptor; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D017493:Leukocyte Common Antigens; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1