Human Adenovirus-Specific c/d and CD8 T Cells Generated by T-Cell Receptor Transfection to Treat Adenovirus Infection after Allogeneic Stem Cell Transplantation

Abstract

Human adenovirus infection is life threatening after allogeneic haematopoietic stem cell transplantation (HSCT). Immunotherapy with donor-derived adenovirus-specific T cells is promising; however, 20% of all donors lack adenovirusspecific T cells. To overcome this, we transfected a/b T cells with mRNA encoding a T-cell receptor (TCR) specific for the HLAA*0101-restricted peptide LTDLGQNLLY from the adenovirus hexon protein. Furthermore, since allo-reactive endogenous TCR of donor T lymphocytes would induce graft-versus-host disease (GvHD) in a mismatched patient, we transferred the TCR into c/d T cells, which are not allo-reactive. TCR-transfected c/d T cells secreted low quantities of cytokines after antigen-specific stimulation, which were increased dramatically after co-transfection of CD8a-encoding mRNA. In direct comparison with TCR-transfected a/b T cells, TCR-CD8a-co-transfected c/d T cells produced more tumor necrosis factor (TNF), and lysed peptide-loaded target cells as efficiently. Most importantly, TCR-transfected a/b T cells and TCR-CD8a-cotransfected c/d T cells efficiently lysed adenovirus-infected target cells. We show here, for the first time, that not only a/b T cells but also c/d T cells can be equipped with an adenovirus specificity by TCR-RNA electroporation. Thus, our strategy offers a new means for the immunotherapy of adenovirus infection after allogeneic HSCT. Citation: Dörrie J, Krug C, Hofmann C, Müller I, Wellner V, et al. (2014) Human Adenovirus-Specific c/d and CD8 T Cells Generated by T-Cell Receptor Transfection to Treat Adenovirus Infection after Allogeneic Stem Cell Transplantation. PLoS ONE 9(10): e109944. doi:10.1371/journal.pone.0109944 Editor: Ramon Arens, Leiden University Medical Center, Netherlands Received May 28, 2014; Accepted September 5, 2014; Published October 7, 2014 Copyright: 2014 Dörrie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the German Research Foundation [DFG SCHA-1247/1-1] to NS, www.dfg.de; Bayerisches Immuntherapie-Netzwerk [D2F5121.7.1.1/10/12] to NS and JD, www.bayimmunet.de; and the Children’s Cancer Research Institute in Vienna, Austria to RG, www.science.ccri.at. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: niels.schaft@uk-erlangen.de " These authors are shared senior authors on this work. ¤ Current address: UCLA, Med. Infectious Diseases, Los Angeles, California, United States of America

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@inproceedings{Drrie2014HumanAC, title={Human Adenovirus-Specific c/d and CD8 T Cells Generated by T-Cell Receptor Transfection to Treat Adenovirus Infection after Allogeneic Stem Cell Transplantation}, author={Jan D{\"{o}rrie and Christian Krug and Christian Hofmann and Ina M{\"{u}ller and Verena Wellner and Ilka Knippertz and Stephan Schierer and Simone Thomas and Elke Zipperer and Dieter Printz and Gerhard Fritsch and Gerold Schuler and Niels Schaft and Rene Geyeregger}, year={2014} }