Role of naive and memory T cells in tumor cell lysis mediated by bi-specific antibodies.
Bispecific monoclonal antibodies (Bi-mAb) with specificity for a tumor associated antigen and the CD3 or CD28 antigen on T lymphocytes, respectively, induce activation of resting T lymphocytes and target-specific tumor cell lysis. Former studies had confirmed that T cells expressing the CD45RO "memory" antigen at high levels were the most potent effectors of Bi-mAb-mediated cytotoxicity when compared to their "naive" counterparts expressing the CD45RA antigen. Further analysis of the T cell subpopulations revealed that within the memory T cell pool, CD8+ T cells were the effector cell, population with strongest cytolytic activity. The cytolytic activity was correlated with the expression level of perforin and granzymes B mRNA. Ca2+ complexing agents, which abrogate perforin activity, reduced necrosis, while inhibition of granzyme activity in effector or target-cells had a similar effect on apoptosis. These results confirm the crucial role perforin and granzymes play in target-cell lysis and explain why CD8+CD45RO+ T cells activated by combined CD3 and CD28 antigen triggering represent the T cell pool with highest cytolytic potential.
Renner
C
C
Department of Hematology and Oncology, University of Saarland, Homburg/Saar, Germany.
Held
G
G
Ohnesorge
S
S
Bauer
S
S
Gerlach
K
K
Pfitzenmeier
J P
JP
Pfreundschuh
M
M
D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007156:Immunologic Memory; D007399:Interphase / Q000276:immunology*; D017730:Ki-1 Antigen / Q000276:immunology; D008213:Lymphocyte Activation; D016131:Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D018106:CD28 Antigens; D017252:CD3 Complex; D017730:Ki-1 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D015842:Serine Proteinase Inhibitors; D054353:Perforin