T-cell-mediated lysis of B cells induced by a CD19xCD3 bispecific single-chain antibody is perforin dependent and death receptor independent.
A recently developed bispecific antibody construct, directed against CD19 and CD3 (bscCD19xCD3), induces T-cell-mediated lysis of allogeneic and autologous B cells in a specific and highly efficient manner. Since knowledge of the molecular mechanisms underlying this lysis is limited, a study on bscCD19xCD3-activated T-cell-effector pathways was performed. BscCD19xCD3-induced lysis of target B-cell lines Nalm-6, Daudi, and Raji and of autologous primary B cells is caused by the perforin-dependent granule-exocytosis pathway but not by the death ligands FasL, TRAIL, or TNF-alpha. When activated by bscCD19xCD3 and Raji cells, T cells express FasL mRNA, but incubation of Raji cells with cell-free supernatants from cytotoxicity experiments caused an upregulation of c-Flipl, possibly accounting for the cells' insensitivity toward death-receptor-mediated lysis. In addition to granule exocytosis, Raji cells are lysed by at least one mechanism independent of perforin, which requires transport through the T cell's Golgi apparatus.
Gruen
Michael
M
Department of Hematology, Oncology and Tumorimmunology, Robert Rössle Clinic, Charité, Humboldt University of Berlin, Berlin, Germany.
Bommert
Kurt
K
Bargou
Ralf C
RC
D018033:Antibodies, Bispecific / Q000276:immunology*; D018941:Antigens, CD19 / Q000276:immunology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000276:immunology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex / Q000276:immunology*; D002352:Carrier Proteins / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis; D053222:Fas Ligand Protein; D006801:Humans; D007167:Immunotherapy; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D017252:CD3 Complex; C506386:CFLAR protein, human; D002352:Carrier Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin