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, G. Vereb, Peter Nagy, J. Szöllősi, 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 2011

Fingerprint

T-Cell Receptor Genes
T-Cell Antigen Receptor
Transgenes
Genetic Therapy
Synapses
T-Lymphocytes
Antigens
Jurkat Cells

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

T-cell synapse formation depends on antigen recognition but not CD3 interaction : Studies with TCR:ζ, a candidate transgene for TCR gene therapy. / Roszik, János; Sebestyén, Zsolt; Govers, Coen; Guri, Yakir; Szöor, Árpád; Pályi-Krekk, Zsuzsanna; Vereb, G.; Nagy, Peter; Szöllősi, J.; Debets, Reno.

In: European Journal of Immunology, Vol. 41, No. 5, 05.2011, p. 1288-1297.

Research output: Contribution to journalArticle

Roszik, János ; Sebestyén, Zsolt ; Govers, Coen ; Guri, Yakir ; Szöor, Árpád ; Pályi-Krekk, Zsuzsanna ; Vereb, G. ; Nagy, Peter ; Szöllősi, J. ; Debets, Reno. / T-cell synapse formation depends on antigen recognition but not CD3 interaction : Studies with TCR:ζ, a candidate transgene for TCR gene therapy. In: European Journal of Immunology. 2011 ; Vol. 41, No. 5. pp. 1288-1297.
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