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The Journal of Immunology, 2007, 179: 4959-4968.
Copyright © 2007 by The American Association of Immunologists, Inc.
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Functional Human Antigen-Specific T Cells Produced In Vitro Using Retroviral T Cell Receptor Transfer into Hematopoietic Progenitors1

Anja U. van Lent*, Maho Nagasawa*, Marleen M. van Loenen{dagger}, Remko Schotte{ddagger}, Ton N. M. Schumacher{ddagger}, Mirjam H. M. Heemskerk{dagger}, Hergen Spits2,* and Nicolas Legrand3,*

* Department of Cell Biology and Histology, Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands; {dagger} Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; and {ddagger} Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

In vitro production of human T cells with known Ag specificity is of major clinical interest for immunotherapy against tumors and infections. We have performed TCR{alpha}beta gene transfer into human hemopoietic progenitors from postnatal thymus or umbilical cord blood, and subsequently cultured these precursors on OP9 stromal cells expressing the Notch human ligand Delta-like1. We report here that fully mature, functional T cells with controlled Ag specificity are obtained from such cultures. Using vectors encoding TCR{alpha}beta-chains directed against melanoma (MART-1), viral (CMV), and minor histocompatibility (HA-2) Ags, we show that the obtained Ag-specific T cells exert cytolytic activity against their cognate Ag and expand in vitro upon specific TCR stimulation. Therapeutic applications may arise from these results because they provide a way to produce large numbers of autologous mature Ag-specific T cells in vitro from undifferentiated hemopoietic progenitors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by grants from the Landsteiner Foundation for Blood Transfusion Research (LSBR, Grant 2003-1365) and the Dutch Cancer Society (KWF; Grant NKI 2006-3530).

2 Current address: Genentech, 1 DNA Way, South San Francisco, CA 94080.

3 Address correspondence and reprint requests to Dr. Nicolas Legrand, Department of Cell Biology and Histology, Academic Medical Center, Meibergdreef 15, Amsterdam, The Netherlands. E-mail address: n.legrand{at}amc.uva.nl

4 Abbreviations used in this paper: NP, nucleoprotein; HSC, hematopoietic stem cell; DL1, Delta-like 1; PNT, post-natal thymus; UCB, umbilical cord blood; YFP, yellow fluorescent protein; SP, single positive; pAg, antigenic peptide; BM, bone marrow; IRES, internal ribosomal entry site; BDCA2, blood dendritic cell antigen; LCL, lymphoblastoid cell line.


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The JI 2007 179: 4951-4952. [Full Text]  





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