Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies

The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical inve...

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Autores: Rujas Díez, Edurne, Cui, Hong, Sicard, Taylor, Semesi, Anthony, Julien, Jean-Philippe
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/50139
Acceso en línea:http://hdl.handle.net/10810/50139
Access Level:acceso abierto
Palabra clave:inducible costimulatory molecule
receptor-binding site
crystal-structure
co-stimulation
cell differentiation
T-cells
ICOS
ligand
activation
expression
id ES_a9a2bbcf91640118fb659d41f2f52fc8
oai_identifier_str oai:addi.ehu.eus:10810/50139
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
title Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
spellingShingle Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
Rujas Díez, Edurne
inducible costimulatory molecule
receptor-binding site
crystal-structure
co-stimulation
cell differentiation
T-cells
ICOS
ligand
activation
expression
title_short Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
title_full Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
title_fullStr Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
title_full_unstemmed Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
title_sort Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic Antibodies
dc.creator.none.fl_str_mv Rujas Díez, Edurne
Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author Rujas Díez, Edurne
author_facet Rujas Díez, Edurne
Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author_role author
author2 Cui, Hong
Sicard, Taylor
Semesi, Anthony
Julien, Jean-Philippe
author2_role author
author
author
author
dc.contributor.none.fl_str_mv European Commission
dc.subject.none.fl_str_mv inducible costimulatory molecule
receptor-binding site
crystal-structure
co-stimulation
cell differentiation
T-cells
ICOS
ligand
activation
expression
topic inducible costimulatory molecule
receptor-binding site
crystal-structure
co-stimulation
cell differentiation
T-cells
ICOS
ligand
activation
expression
description The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Ao resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors. The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, binding its ligand (ICOS-L) on activated T cells. The structure of the ICOS/ICOS-L complex reveals a distinct receptor binding orientation. The structures of ICOS and ICOS-L in complex with potentially therapeutic antibodies suggest the structural basis of such antibodies' efficacies and high binding affinities.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/50139
url http://hdl.handle.net/10810/50139
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/EC/H2020/790012
https://www.nature.com/articles/s41467-020-18828-4
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature
publisher.none.fl_str_mv Nature
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Structural Characterization of the ICOS/ICOS-L Immune Complex Reveals High Molecular Mimicry by Therapeutic AntibodiesRujas Díez, EdurneCui, HongSicard, TaylorSemesi, AnthonyJulien, Jean-Philippeinducible costimulatory moleculereceptor-binding sitecrystal-structureco-stimulationcell differentiationT-cellsICOSligandactivationexpressionThe inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, and delivers a positive co-stimulatory signal to activated T cells upon binding to its ligand (ICOS-L). Dysregulation of this pathway has been implicated in autoimmune diseases and cancer, and is currently under clinical investigation as an immune checkpoint blockade. Here, we describe the molecular interactions of the ICOS/ICOS-L immune complex at 3.3 Ao resolution. A central FDPPPF motif and residues within the CC' loop of ICOS are responsible for the specificity of the interaction with ICOS-L, with a distinct receptor binding orientation in comparison to other family members. Furthermore, our structure and binding data reveal that the ICOS N110 N-linked glycan participates in ICOS-L binding. In addition, we report crystal structures of ICOS and ICOS-L in complex with monoclonal antibodies under clinical evaluation in immunotherapy. Strikingly, antibody paratopes closely mimic receptor-ligand binding core interactions, in addition to contacting peripheral residues to confer high binding affinities. Our results uncover key molecular interactions of an immune complex central to human adaptive immunity and have direct implications for the ongoing development of therapeutic interventions targeting immune checkpoint receptors. The inducible co-stimulator (ICOS) is a member of the CD28/B7 superfamily, binding its ligand (ICOS-L) on activated T cells. The structure of the ICOS/ICOS-L complex reveals a distinct receptor binding orientation. The structures of ICOS and ICOS-L in complex with potentially therapeutic antibodies suggest the structural basis of such antibodies' efficacies and high binding affinities.This work was supported by the European Union's Horizon 2020 research and innovation program under Marie Sklodowska-Curie grant 790012 (E.R.), by operating grant PJT-148811 from the Canadian Institutes of Health Research (J.P.J.), the CIFAR Azrieli Global Scholar program (J.P.J.), the Ontario Early Researcher Awards program (J.P.J.), and the Canada Research Chairs program (J.P.J.). T.S. is a recipient of a Vanier Canada Graduate Scholarship. The BLI instrument was accessed at the Structural & Biophysical Core Facility, The Hospital for Sick Children, supported by the Canada Foundation for Innovation and Ontario Research Fund. X-ray diffraction experiments were performed at GM/CA@APS, which has been funded in whole or in part with federal funds from the National Cancer Institute (ACB-12002) and the National Institute of General Medical Sciences (AGM -12006). The Eiger 16M detector at GM/CA-XSD was funded by NIH grant S10 OD012289. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science user facility operated for the DOE Office of Science by Argonne National Laboratory under contract DE-ACO2-06CH11357. X-ray diffraction experiments were also performed at the NSLS-II, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by BNL under Contract No. DE -5C0012704. The Life Science Biomedical Technology Research resource is primarily supported by the National Institute of Health, National Institute of General Medical Sciences (NIGMS) through a Biomedical Technology Research Resource P41 grant (P41GM111244), and by the DOE Office of Biological and Environmental Research (KP1605010).NatureEuropean Commission202120212020info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/50139reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/EC/H2020/790012https://www.nature.com/articles/s41467-020-18828-4info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/This article is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0)Atribución 3.0 Españaoai:addi.ehu.eus:10810/501392026-06-18T09:23:17Z
score 15,301603

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