NDLI: T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Perez-Chacon, Gema Morales-Kastresana, Aizea Azpilikueta, Arantza Jure-Kunkel, Maria Palazon, Asis Teijeira, Alvaro Zapata, Juan M. Martinez-Forero, Ivan Melero, Ignacio Murillo, Oihana Bolaños-Mateo, Elixabet Nistal-Villan, Estanislao
Description	Country affiliation: Spain Author Affiliation: Martinez-Forero I ( Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona 31008, Spain.)
Abstract	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.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	12
Volume Number	190
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2013-06-15
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Antibodies, Monoclonal Immunology Antigens, Cd137 Metabolism Lymphocyte Activation Neoplasms, Experimental T-lymphocytes Animals Pharmacology Blotting, Western Cell Line Endocytosis Drug Effects Endosomes Immunoprecipitation Immunotherapy Mice Mice, Inbred Balb C Mice, Inbred C57bl Mice, Transgenic Nf-kappa B Therapy Polyubiquitin Signal Transduction Tnf Receptor-associated Factor 2 Transfection Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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