Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction

Shengdian Wang, Jürgen Bajorath, Dallas B. Flies, Haidong Dong, Tasuku Honjo, Lieping Chen

Research output: Contribution to journalArticle

237 Scopus citations

Abstract

B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A′GFCC′C″ face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1 - deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.

Original languageEnglish (US)
Pages (from-to)1083-1091
Number of pages9
JournalJournal of Experimental Medicine
Volume197
Issue number9
DOIs
StatePublished - May 5 2003

Keywords

  • Costimulation
  • Mutagenesis
  • PD-1 ligands
  • T cell activation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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