International Immunology Advance Access originally published online on February 28, 2006
International Immunology 2006 18(4):591-601; doi:10.1093/intimm/dxh401
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
T cell re-targeting to EBV antigens following TCR gene transfer: CD28-containing receptors mediate enhanced antigen-specific IFN
production
1 Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA Rotterdam, the Netherlands
2 Tumor Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, University of Queensland, Brisbane, Australia
3 Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden
4 INSERM U463, Institut de Biologie, Nantes, France
5 Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Birmingham, UK
6 MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK
7 Present address: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany
8 Present address: Archifact, Meerewijck 79, 2451 XC Leimuiden, the Netherlands
Correspondence to: R. Debets; E-mail: j.debets{at}erasmusmc.nl
EBV is associated with a broad range of malignancies. Adoptive immunotherapy of these tumors with EBV-specific CTL proved useful. We generated a panel of primary human T cells specific to various EBV antigens (i.e. Epstein–Barr nuclear antigen 3A, 3B and BamHI-M leftward reading frame) via transfer of modified TCR genes that are either coupled to CD3
or Fc(
)RI
. TCR-transduced T cells from 20–60% of donors (total number of 25) demonstrated specific lysis of EBV peptide-loaded target cells, whereas lymphoblastoid cell lines expressing native EBV antigens were not killed by any of the EBV-specific T cell populations. This non-responsiveness, confirmed at the level of nuclear factor of activated T cells activation, is not due to receptor configuration since identical receptor formats specific for melanoma antigens successfully re-targeted T cells to native melanoma cells. In an effort to generate a more potent receptor, we introduced a CD28 domain into one of the EBV-specific TCR. This TCR did not affect the cytotoxic response of re-targeted T cells, but dramatically enhanced antigen-specific IFN production. We therefore conclude that these novel CD28-containing EBV-specific TCRs provide a basis for further development of TCR gene transfer to treat EBV-induced diseases.
Keywords: cytotoxicity, gene therapy, signal transduction, T cell co-stimulation, tumor immunity
Transmitting editor: L. Lanier
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Sebestyen, E. Schooten, T. Sals, I. Zaldivar, E. San Jose, B. Alarcon, S. Bobisse, A. Rosato, J. Szollosi, J. W. Gratama, et al. Human TCR That Incorporate CD3{zeta} Induce Highly Preferred Pairing between TCR{alpha} and {beta} Chains following Gene Transfer J. Immunol., June 1, 2008; 180(11): 7736 - 7746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W Yang, E. Beaudoin, L Lu, R. Du Pasquier, M. Kuroda, R. Willemsen, I. Koralnik, and R. Junghans Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML) Int. Immunol., September 1, 2007; 19(9): 1083 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. MacArthur, A. D. Wilson, M. A. Birchall, and A. J. Morgan Primary CD4+ T-Cell Responses Provide both Helper and Cytotoxic Functions during Epstein-Barr Virus Infection and Transformation of Fetal Cord Blood B Cells J. Virol., May 1, 2007; 81(9): 4766 - 4775. [Abstract] [Full Text] [PDF]
|
|