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Journal of Immunology
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T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes / Iván Martínez Forero
Título : T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes Tipo de documento : documento electrónico Autores : Iván Martínez Forero, Fecha de publicación : 2013 Títulos uniformes : Journal of Immunology Idioma : Inglés (eng) Resumen : Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients. Mención de responsabilidad : Ivan Martinez-Forero, Arantza Azpilikueta, Elixabet Bolaños-Mateo, Estanislao Nistal-Villan, Asis Palazon, Alvaro Teijeira, Gema Perez-Chacon, Aizea Morales-Kastresana, Oihana Murillo, Maria Jure-Kunkel, Juan M Zapata, Ignacio Melero Referencia : J Immunol. 2013 Jun 15;190(12):6694-706. DOI (Digital Object Identifier) : 10.4049/jimmunol.1203010 PMID : 23690480 En línea : https://www.jimmunol.org/content/190/12/6694 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3675 T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes [documento electrónico] / Iván Martínez Forero, . - 2013.
Obra : Journal of Immunology
Idioma : Inglés (eng)
Resumen : Agonist anti-CD137 (4-1BB) mAbs enhance CD8-mediated antitumor immunity. Agonist anti-human CD137 mAbs binding to four distinct epitopes on the CD137 glycoprotein costimulated T cell activation irrespective of the engaged epitope or its interference with CD137L binding. CD137 perturbation with all these agonist mAbs resulted in Ag and Ab internalization toward an endosomal vesicular compartment. Internalization was observed in activated T lymphocytes from humans and mice, not only in culture but also in Ab-injected living animals. These in vivo experiments were carried out upon systemic i.v. injections with anti-CD137 mAbs and showed CD137 internalization in tumor-infiltrating lymphocytes and in activated human T cells transferred to immunodeficient mice. Efficient CD137 internalization required K63 polyubiquitination and endocytosed CD137-containing vesicles recruited TNFR-associated factor (TRAF) 2 and were decorated with K63 polyubiquitins. CD137 stimulation activates NF-κB through a K63-linked polyubiquitination-dependent route, and CD137-associated TRAF2 becomes K63 polyubiquitinated. Consistent with a role for TRAF2 in CD137 signaling, transgenic mice functionally deficient in TRAF2 showed delayed immunotherapeutic activity of anti-CD137 mAbs. As a whole, these findings advance our knowledge of the mechanisms of action of anti-CD137 immunostimulatory mAbs such as those currently undergoing clinical trials in cancer patients. Mención de responsabilidad : Ivan Martinez-Forero, Arantza Azpilikueta, Elixabet Bolaños-Mateo, Estanislao Nistal-Villan, Asis Palazon, Alvaro Teijeira, Gema Perez-Chacon, Aizea Morales-Kastresana, Oihana Murillo, Maria Jure-Kunkel, Juan M Zapata, Ignacio Melero Referencia : J Immunol. 2013 Jun 15;190(12):6694-706. DOI (Digital Object Identifier) : 10.4049/jimmunol.1203010 PMID : 23690480 En línea : https://www.jimmunol.org/content/190/12/6694 Enlace permanente : https://hospitalpablotobon.cloudbiteca.com/pmb/opac_css/index.php?lvl=notice_display&id=3675 Reserva
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