Cargando…
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...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545189/ https://www.ncbi.nlm.nih.gov/pubmed/33033255 http://dx.doi.org/10.1038/s41467-020-18828-4 |
_version_ | 1783591984053616640 |
---|---|
author | Rujas, Edurne Cui, Hong Sicard, Taylor Semesi, Anthony Julien, Jean-Philippe |
author_facet | Rujas, Edurne Cui, Hong Sicard, Taylor Semesi, Anthony Julien, Jean-Philippe |
author_sort | Rujas, Edurne |
collection | PubMed |
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 Å 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. |
format | Online Article Text |
id | pubmed-7545189 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-75451892020-10-19 Structural characterization of the ICOS/ICOS-L immune complex reveals high molecular mimicry by therapeutic antibodies Rujas, Edurne Cui, Hong Sicard, Taylor Semesi, Anthony Julien, Jean-Philippe Nat Commun Article 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 Å 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. Nature Publishing Group UK 2020-10-08 /pmc/articles/PMC7545189/ /pubmed/33033255 http://dx.doi.org/10.1038/s41467-020-18828-4 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rujas, Edurne Cui, Hong Sicard, Taylor Semesi, Anthony Julien, Jean-Philippe 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 |
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_short | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545189/ https://www.ncbi.nlm.nih.gov/pubmed/33033255 http://dx.doi.org/10.1038/s41467-020-18828-4 |
work_keys_str_mv | AT rujasedurne structuralcharacterizationoftheicosicoslimmunecomplexrevealshighmolecularmimicrybytherapeuticantibodies AT cuihong structuralcharacterizationoftheicosicoslimmunecomplexrevealshighmolecularmimicrybytherapeuticantibodies AT sicardtaylor structuralcharacterizationoftheicosicoslimmunecomplexrevealshighmolecularmimicrybytherapeuticantibodies AT semesianthony structuralcharacterizationoftheicosicoslimmunecomplexrevealshighmolecularmimicrybytherapeuticantibodies AT julienjeanphilippe structuralcharacterizationoftheicosicoslimmunecomplexrevealshighmolecularmimicrybytherapeuticantibodies |