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Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function
Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand bindin...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2002
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193694/ https://www.ncbi.nlm.nih.gov/pubmed/11956294 http://dx.doi.org/10.1084/jem.20011607 |
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author | Wang, Shengdian Zhu, Gefeng Tamada, Koji Chen, Lieping Bajorath, Jürgen |
author_facet | Wang, Shengdian Zhu, Gefeng Tamada, Koji Chen, Lieping Bajorath, Jürgen |
author_sort | Wang, Shengdian |
collection | PubMed |
description | Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic “PPP” sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor–ligand interaction and provide new modulators for immune responses. |
format | Text |
id | pubmed-2193694 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21936942008-04-14 Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function Wang, Shengdian Zhu, Gefeng Tamada, Koji Chen, Lieping Bajorath, Jürgen J Exp Med Article Interaction between inducible costimulator (ICOS) and its ligand is implicated in the induction of cell-mediated and humoral immune responses. However, the molecular details of this interaction are unknown. We report here a mutagenesis analysis of residues in ICOS that are critical for ligand binding. A three-dimensional model of the extracellular immunoglobulin-like domain of ICOS was used to map the residues conserved within the CD28 family. This analysis identified a surface patch containing the characteristic “PPP” sequence and is conserved in human and mouse ICOS. Mutations in this region of human ICOS reduce or abolish ligand binding. Our results suggest that the ligand binding site in ICOS maps to a region overlapping yet distinct from the CD80/CD86 binding sites in CD28 and cytotoxic T lymphocyte antigen (CTLA)-4. Thus, the analysis suggests that differences in ligand binding specificity between these related costimulatory molecules have evolved by utilization of overlapping regions with different patterns of conserved and nonconserved residues. Two site-specific mutants generated in the course of our studies bound ICOS ligand with higher avidity than wild-type ICOS. An S76E mutant protein of ICOS blocked T cell costimulatory function of ICOS ligand and inhibited T cell response to allogeneic antigens superior to wild-type ICOS. Our studies thus identified critical residues involving in ICOS receptor–ligand interaction and provide new modulators for immune responses. The Rockefeller University Press 2002-04-15 /pmc/articles/PMC2193694/ /pubmed/11956294 http://dx.doi.org/10.1084/jem.20011607 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Wang, Shengdian Zhu, Gefeng Tamada, Koji Chen, Lieping Bajorath, Jürgen Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title | Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title_full | Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title_fullStr | Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title_full_unstemmed | Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title_short | Ligand Binding Sites of Inducible Costimulator and High Avidity Mutants with Improved Function |
title_sort | ligand binding sites of inducible costimulator and high avidity mutants with improved function |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193694/ https://www.ncbi.nlm.nih.gov/pubmed/11956294 http://dx.doi.org/10.1084/jem.20011607 |
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