T-cell synapse formation depends on antigen recognition but not CD3 interaction: Studies with TCR:ζ, a candidate transgene for TCR gene therapy

János Roszik, Zsolt Sebestyén, Coen Govers, Yakir Guri, Árpád Szöor, Zsuzsanna Pályi-Krekk, György Vereb, Peter Nagy, János Szöllosi, Reno Debets

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

T-cell receptors (TCRs) can be genetically modified to improve gene-engineered T-cell responses, a strategy considered critical for the success of clinical TCR gene therapy to treat cancers. TCR:ζ, which is a heterodimer of TCRα and β chains each coupled to complete human CD3ζ, overcomes issues of mis-pairing with endogenous TCR chains, shows high surface expression and mediates antigen-specific T-cell functions in vitro. In the current study, we further characterized TCR:ζ in gene-engineered T cells and assessed whether this receptor is able to interact with surface molecules and drive correct synapse formation in Jurkat T cells. The results showed that TCR:ζ mediates the formation of synaptic areas with antigen-positive target cells, interacts closely with CD8α and MHC class I (MHCI), and co-localizes with CD28, CD45 and lipid rafts, similar to WT TCR. TCR:ζ did not closely associate with endogenous CD3ε, despite its co-presence in immune synapses, and TCR:ζ showed enhanced synaptic accumulation in T cells negative for surface-expressed TCR molecules. Notably, synaptic TCR:ζ demonstrated lowered densities when compared with TCR in dual TCR T cells, a phenomenon that was related to both extracellular and intracellular CD3ζ domains present in the TCR:ζ molecule and responsible for enlarged synapse areas.

Original languageEnglish
Pages (from-to)1288-1297
Number of pages10
JournalEuropean journal of immunology
Volume41
Issue number5
DOIs
Publication statusPublished - May 1 2011

Keywords

  • Adoptive T-cell therapy
  • CD3
  • Fluorescence resonance energy transfer
  • Immune synapse
  • TCR:ζ

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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