Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML)

W. Yang, E. L. Beaudoin, L. Lu, R. A. Du Pasquier, M. J. Kuroda, R. A. Willemsen, I. J. Koralnik, R. P. Junghans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Progressive multifocal leukoencephalopathy (PML) is a deadly brain disease caused by the polyomavirus JC (JCV). The aim of this study is to develop 'designer T cells' armed with anti-JCV TCR-based chimeric immune receptors (CIRs) by gene modification for PML immunotherapy. Two T cell lines specific to two dominant CTL epitopes derived from JCV VP1 protein (termed p36 and p100) from an HLA-A0201+ PML survivor were generated for TCR cloning. Two distinct dominant TCR alpha chains (Vα6 and Vα12) and a unique TCR beta chain (Vβ5.1) were cloned from the p36-specific cell line, while only one alpha (Vα8.6) and one beta (Vβ2) chains were dominant in the p100-specific line. Retroviral constructs encoding CIRs were created with the extracellular domains of TCR α and β chains fused to the transmembrane and cytoplasmic portions of CD3ζ (VαCαCD3ζ or VβCβCD3ζ). Cellular expression and screening for binding specific peptide-HLA-A0201 tetramer confirmed the reactivity of the p100 TCRαβ and of one of the two pairs of p36 TCRαβ (Vα12 and Vβ5.1). Functional tests confirmed CIR-expressing T cells secreted cytokines and expressed potent cytotoxicity on contact with A0201+ B-lymphoblastoid line loaded with peptides and/or with HLA-A0201+ cells expressing native JCV VP1 protein. In conclusion, anti-JCV designer T cells were generated.

Original languageEnglish (US)
Pages (from-to)1083-1093
Number of pages11
JournalInternational Immunology
Volume19
Issue number9
DOIs
StatePublished - Sep 2007

Keywords

  • Gene transfer
  • Retroviral transduction
  • T cell
  • TCR

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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