Transgenic TCR expression: Comparison of single chain with full-length receptor constructs for T-cell function

Tong Zhang, Xianghui He, Tom C. Tsang, David T. Harris

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Genetic modification of T lymphocytes with T-cell receptor (TCR) genes provides a novel tool for adoptive immunotherapy. However, the efficiency of full-length TCR (flTCR)-transduced T cells could be limited by factors such as incorrect pairing between exogenous and endogenous TCR chains and downregulation of the CD3 complex. To overcome these hurdles, one promising strategy is to use three-domain single-chain TCRs (3D-scTCR), in which TCR Vα and Vβ chains are joined by a linker with signal transduction domains fused at the carboxyl termini as signal transducers and amplifiers. Our results showed that surface expression of scTCRs on T cells after retroviral transduction was affected by the origin of the transmembrane (TM) region and placement of signaling domains. scTCR-modified T cells were functional as shown by cytokine (IL-2 and IFN-γ) release in response to antigen stimulation and cytolytic activity against specific target cells. CD8 and CD28, but not the complete CD3 complex, could enhance the scTCR-induced T cell activation. Compared with flTCR-modified T cells and native CTLs, scTCR-modified T cells require higher thresholds of antigen stimulation (∼10-8 M peptide) to be functional. Despite the low efficiency of scTCRs, our data provide insight into further improvements in generating efficient scTCRs for in vivo applications.

Original languageEnglish (US)
Pages (from-to)487-496
Number of pages10
JournalCancer gene therapy
Volume11
Issue number7
DOIs
StatePublished - Jul 1 2004

Keywords

  • Chimeric receptor
  • Signal transduction
  • Single chain
  • TCR

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Transgenic TCR expression: Comparison of single chain with full-length receptor constructs for T-cell function'. Together they form a unique fingerprint.

  • Cite this