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Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell receptor

Gene Therapy volume 11, pages 1234–1239 (2004)Cite this article

Abstract

The T-cell receptor (TCR) determines the specificity of T-cell recognition by binding to peptide fragments of intracellular proteins presented at the cell surface in association with molecules of the major histocompatibility complex (MHC). Engagement of the TCR by its cognate peptide/MHC ligand, with appropriate co-stimulatory signals, leads to activation of T-cell effector functions. Here we show that the attachment proteins of attenuated measles viruses, engineered to display a high-affinity single-chain TCR (scTCR), can recognize and bind to specific peptide–MHC complexes and thereby mediate targeted virus-cell entry and cell-to-cell fusion. Using the 2C TCR and its peptide/MHC ligand (SIYRYYGL/mouse Kb), we show that a scTCR grafted onto the measles virus H protein confers new specificity to virus entry and cell fusion. The efficiency of TCR-mediated virus entry was dependent on the number of peptide/MHC complexes expressed on the target cells, increasing progressively above densities higher than 2500 complexes per cell. This work introduces a new paradigm for targeting virus entry and membrane fusion by extending the repertoire of targets to specific peptide–MHC ligands and offering a novel quantitative readout for the cellular expression of peptide–MHC complexes.

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Acknowledgements

We thank Bryan Cho and Herman Eisen for providing the vector used for endogenous expression of SIYR peptide. This work is supported by the Mayo Foundation, Harold W Siebens Foundation, and George W Eisenberg Foundation (KWP, SJR), and the NIH GM55767 (DMK).

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Author notes

  1. P D Holler

    Present address: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

Authors and Affiliations

  1. Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN, USA

    K-W Peng & S J Russell

  2. Department of Biochemistry, University of Illinois, Urbana, IL, USA

    P D Holler, B A Orr & D M Kranz

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Peng, KW., Holler, P., Orr, B. et al. Targeting virus entry and membrane fusion through specific peptide/MHC complexes using a high-affinity T-cell receptor. Gene Ther 11, 1234–1239 (2004). https://doi.org/10.1038/sj.gt.3302286

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