The affinity of elongated membrane-tethered ligands determines potency of T cell receptor triggering

Bing Mae Chen, Mohammad Ameen Al-Aghbar, Chien Hsin Lee, Tien Ching Chang, Yu-Cheng Su, Ya Chen Li, Shih En Chang, Chin Chuan Chen, Tsai Hua Chung, Yuan Chun Liao, Chau Hwang Lee, Steve R. Roffler*

*Corresponding author for this work

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

T lymphocytes are important mediators of adoptive immunity but the mechanism of T cell receptor (TCR) triggering remains uncertain. The interspatial distance between engaged T cells and antigen-presenting cells (APCs) is believed to be important for topological rearrangement of membrane tyrosine phosphatases and initiation of TCR signaling. We investigated the relationship between ligand topology and affinity by generating a series of artificial APCs that express membrane-tethered anti-CD3 scFv with different affinities (OKT3, BC3, and 2C11) in addition to recombinant class I and II pMHC molecules. The dimensions of membrane-tethered anti-CD3 and pMHC molecules were progressively increased by insertion of different extracellular domains. In agreement with previous studies, elongation of pMHC molecules or low-affinity anti-CD3 scFv caused progressive loss of T cell activation. However, elongation of high-affinity ligands (BC3 and OKT3 scFv) did not abolish TCR phosphorylation and T cell activation. Mutation of key amino acids in OKT3 to reduce binding affinity to CD3 resulted in restoration of topological dependence on T cell activation. Our results show that high-affinity TCR ligands can effectively induce TCR triggering even at large interspatial distances between T cells and APCs.

Original languageEnglish
Article number793
JournalFrontiers in Immunology
Volume8
Issue numberJUL
DOIs
StatePublished - 10 Jul 2017

Keywords

  • 2C11
  • Affinity
  • Anti-CD3 scFv
  • Artificial antigen-presenting cell
  • BC3
  • OKT3
  • PMHC
  • T cell receptor triggering

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