Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains

D. H. Aggen, A. S. Chervin, T. M. Schmitt, B. Engels, J. D. Stone, S. A. Richman, K. H. Piepenbrink, B. M. Baker, P. D. Greenberg, H. Schreiber, David M Kranz

Research output: Contribution to journalArticle

Abstract

Transduction of exogenous T-cell receptor (TCR) genes into patients' activated peripheral blood T cells is a potent strategy to generate large numbers of specific T cells for adoptive therapy of cancer and viral diseases. However, the remarkable clinical promise of this powerful approach is still being overshadowed by a serious potential consequence: mispairing of the exogenous TCR chains with endogenous TCR chains. These 'mixed' heterodimers can generate new specificities that result in graft-versus-host reactions. Engineering TCR constant regions of the exogenous chains with a cysteine promotes proper pairing and reduces the mispairing, but, as we show here, does not eliminate the formation of mixed heterodimers. By contrast, deletion of the constant regions, through use of a stabilized Vα/VΒ single-chain TCR (scTv), avoided mispairing completely. By linking a high-affinity scTv to intracellular signaling domains, such as Lck and CD28, the scTv was capable of activating functional T-cell responses in the absence of either the CD3 subunits or the co-receptors, and circumvented mispairing with endogenous TCRs. Such transduced T cells can respond to the targeted antigen independent of CD3 subunits via the introduced scTv, without the transduced T cells acquiring any new undefined and potentially dangerous specificities.

Original languageEnglish (US)
Pages (from-to)365-374
Number of pages10
JournalGene therapy
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2012

Fingerprint

T-Cell Antigen Receptor
T-Lymphocytes
CD3 Antigens
T-Cell Receptor Genes
Virus Diseases
Cell- and Tissue-Based Therapy
Cysteine
Blood Cells
Transplants
Neoplasms

Keywords

  • T-cell receptors
  • adoptive T-cell therapy
  • peptide/MHC
  • retroviral transduction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Aggen, D. H., Chervin, A. S., Schmitt, T. M., Engels, B., Stone, J. D., Richman, S. A., ... Kranz, D. M. (2012). Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains. Gene therapy, 19(4), 365-374. https://doi.org/10.1038/gt.2011.104

Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains. / Aggen, D. H.; Chervin, A. S.; Schmitt, T. M.; Engels, B.; Stone, J. D.; Richman, S. A.; Piepenbrink, K. H.; Baker, B. M.; Greenberg, P. D.; Schreiber, H.; Kranz, David M.

In: Gene therapy, Vol. 19, No. 4, 01.04.2012, p. 365-374.

Research output: Contribution to journalArticle

Aggen, DH, Chervin, AS, Schmitt, TM, Engels, B, Stone, JD, Richman, SA, Piepenbrink, KH, Baker, BM, Greenberg, PD, Schreiber, H & Kranz, DM 2012, 'Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains', Gene therapy, vol. 19, no. 4, pp. 365-374. https://doi.org/10.1038/gt.2011.104
Aggen DH, Chervin AS, Schmitt TM, Engels B, Stone JD, Richman SA et al. Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains. Gene therapy. 2012 Apr 1;19(4):365-374. https://doi.org/10.1038/gt.2011.104
Aggen, D. H. ; Chervin, A. S. ; Schmitt, T. M. ; Engels, B. ; Stone, J. D. ; Richman, S. A. ; Piepenbrink, K. H. ; Baker, B. M. ; Greenberg, P. D. ; Schreiber, H. ; Kranz, David M. / Single-chain VαVβ T-cell receptors function without mispairing with endogenous TCR chains. In: Gene therapy. 2012 ; Vol. 19, No. 4. pp. 365-374.
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