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Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells

Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted... Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells Kristian Riesbeck 1 , 2 , * , Anita Billström 1 , Jesper Tordsson 1 , Thomas Brodin 1 , Karin Kristensson 1 , and Mikael Dohlsten 1 , † Active Biotech, Lund Research Center, Lund, 1 and Department of Medical Microbiology, Malmö University Hospital, Lund University, Malmö, 2 Sweden ABSTRACT The objective of this study was to investigate whether the superantigen staphylococcal enterotoxin A (SEA), which binds to HLA class II and T-cell receptor Vβ chains, can direct cytotoxic T cells to lyse cytokine-stimulated endothelial cells (EC). In addition, we wanted to determine whether SEA-primed cytotoxic T cells could be targeted to EC surface molecules as a means of a novel cancer immunotherapy. Human umbilical vein EC (HUVEC), dermal microvascular EC (HMVEC), or the EC line EA.hy926 stimulated with gamma interferon (IFN-γ) or tumor necrosis factor alpha (TNF-α) displayed upregulated HLA class II and adhesion molecule (CD54 and CD106) expression, respectively. SEA-primed T cells induced a strong cytotoxicity against IFN-γ- and TNF-α-activated EA.hy926 which had been preincubated with SEA. Blocking of CD54 completely abrogated the T-cell attack. SEA-D227A, which has a mutated class II binding site, did not promote any cytotoxicity. A strong lysis was observed when a fusion protein consisting of protein A and SEA-D227A was added together with T cells to TNF-α-induced EA.hy926 and HUVEC precoated with monoclonal antibodies (MAb) directed against HLA class I, CD54, or CD106 molecules. Finally, an scFv antibody fragment reactive with an unknown EC antigen was fused with SEA-D227A. Both EA.hy926 and HMVEC were efficiently lysed by scFv-SEA-D227A-triggered cytotoxic T cells. Taken together, superantigen-activated T-cell-dependent EC killing was induced when EC expressed an inflammatory phenotype. Moreover, specific MAb targeting of the superantigen to surface antigens induced EC lysis. Our data suggest that directed T-cell-mediated lysis of unwanted proliferating EC, such as those in the tumor microvasculature, can be clinically useful. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical and Vaccine Immunology American Society For Microbiology

Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells

Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells

Clinical and Vaccine Immunology , Volume 5 (5): 675 – Sep 1, 1998

Abstract

Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells Kristian Riesbeck 1 , 2 , * , Anita Billström 1 , Jesper Tordsson 1 , Thomas Brodin 1 , Karin Kristensson 1 , and Mikael Dohlsten 1 , † Active Biotech, Lund Research Center, Lund, 1 and Department of Medical Microbiology, Malmö University Hospital, Lund University, Malmö, 2 Sweden ABSTRACT The objective of this study was to investigate whether the superantigen staphylococcal enterotoxin A (SEA), which binds to HLA class II and T-cell receptor Vβ chains, can direct cytotoxic T cells to lyse cytokine-stimulated endothelial cells (EC). In addition, we wanted to determine whether SEA-primed cytotoxic T cells could be targeted to EC surface molecules as a means of a novel cancer immunotherapy. Human umbilical vein EC (HUVEC), dermal microvascular EC (HMVEC), or the EC line EA.hy926 stimulated with gamma interferon (IFN-γ) or tumor necrosis factor alpha (TNF-α) displayed upregulated HLA class II and adhesion molecule (CD54 and CD106) expression, respectively. SEA-primed T cells induced a strong cytotoxicity against IFN-γ- and TNF-α-activated EA.hy926 which had been preincubated with SEA. Blocking of CD54 completely abrogated the T-cell attack. SEA-D227A, which has a mutated class II binding site, did not promote any cytotoxicity. A strong lysis was observed when a fusion protein consisting of protein A and SEA-D227A was added together with T cells to TNF-α-induced EA.hy926 and HUVEC precoated with monoclonal antibodies (MAb) directed against HLA class I, CD54, or CD106 molecules. Finally, an scFv antibody fragment reactive with an unknown EC antigen was fused with SEA-D227A. Both EA.hy926 and HMVEC were efficiently lysed by scFv-SEA-D227A-triggered cytotoxic T cells. Taken together, superantigen-activated T-cell-dependent EC killing was induced when EC expressed an inflammatory phenotype. Moreover, specific MAb targeting of the superantigen to surface antigens induced EC lysis. Our data suggest that directed T-cell-mediated lysis of unwanted proliferating EC, such as those in the tumor microvasculature, can be clinically useful.

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Publisher
American Society For Microbiology
Copyright
Copyright © 1998 by the American society for Microbiology.
ISSN
1556-6811
eISSN
1556-679X
Publisher site
See Article on Publisher Site

Abstract

Endothelial Cells Expressing an Inflammatory Phenotype Are Lysed by Superantigen-Targeted Cytotoxic T Cells Kristian Riesbeck 1 , 2 , * , Anita Billström 1 , Jesper Tordsson 1 , Thomas Brodin 1 , Karin Kristensson 1 , and Mikael Dohlsten 1 , † Active Biotech, Lund Research Center, Lund, 1 and Department of Medical Microbiology, Malmö University Hospital, Lund University, Malmö, 2 Sweden ABSTRACT The objective of this study was to investigate whether the superantigen staphylococcal enterotoxin A (SEA), which binds to HLA class II and T-cell receptor Vβ chains, can direct cytotoxic T cells to lyse cytokine-stimulated endothelial cells (EC). In addition, we wanted to determine whether SEA-primed cytotoxic T cells could be targeted to EC surface molecules as a means of a novel cancer immunotherapy. Human umbilical vein EC (HUVEC), dermal microvascular EC (HMVEC), or the EC line EA.hy926 stimulated with gamma interferon (IFN-γ) or tumor necrosis factor alpha (TNF-α) displayed upregulated HLA class II and adhesion molecule (CD54 and CD106) expression, respectively. SEA-primed T cells induced a strong cytotoxicity against IFN-γ- and TNF-α-activated EA.hy926 which had been preincubated with SEA. Blocking of CD54 completely abrogated the T-cell attack. SEA-D227A, which has a mutated class II binding site, did not promote any cytotoxicity. A strong lysis was observed when a fusion protein consisting of protein A and SEA-D227A was added together with T cells to TNF-α-induced EA.hy926 and HUVEC precoated with monoclonal antibodies (MAb) directed against HLA class I, CD54, or CD106 molecules. Finally, an scFv antibody fragment reactive with an unknown EC antigen was fused with SEA-D227A. Both EA.hy926 and HMVEC were efficiently lysed by scFv-SEA-D227A-triggered cytotoxic T cells. Taken together, superantigen-activated T-cell-dependent EC killing was induced when EC expressed an inflammatory phenotype. Moreover, specific MAb targeting of the superantigen to surface antigens induced EC lysis. Our data suggest that directed T-cell-mediated lysis of unwanted proliferating EC, such as those in the tumor microvasculature, can be clinically useful.

Journal

Clinical and Vaccine ImmunologyAmerican Society For Microbiology

Published: Sep 1, 1998

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