Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 5, Pages 1288-1297Publisher
WILEY
DOI: 10.1002/eji.200940233
Keywords
Adoptive T-cell therapy; CD3; Fluorescence resonance energy transfer; Immune synapse; TCR:zeta
Categories
Funding
- European Community [EU FP6 LSHB-CT-2004-503467, FP6 LSHC CT-2005-018914, EU FP6 MCRTB-CT-035946 018914, EU FP6 MRTN-CT-2006-019481]
- Hungarian National Development Agency [TAMOP-4.2.2-08/1-2008-0019]
- Hungarian National Research Fund [OTKA K62648, OTKA K75752, OTKA K68763]
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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:zeta, which is a heterodimer of TCR alpha and beta chains each coupled to complete human CD3 zeta, 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:zeta 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:zeta mediates the formation of synaptic areas with antigen-positive target cells, interacts closely with CD8 alpha and MHC class I (MHCI), and co-localizes with CD28, CD45 and lipid rafts, similar to WT TCR. TCR:zeta did not closely associate with endogenous CD3 epsilon, despite its co-presence in immune synapses, and TCR:zeta showed enhanced synaptic accumulation in T cells negative for surface-expressed TCR molecules. Notably, synaptic TCR:zeta demonstrated lowered densities when compared with TCR in dual TCR T cells, a phenomenon that was related to both extracellular and intracellular CD3 zeta domains present in the TCR:zeta molecule and responsible for enlarged synapse areas.
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