Human adenovirus-specific γ/δ 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 adenovirus-specific T cells. To overcome this, we transfected α/β T cells with mRNA encoding a T-cell receptor (TCR) specific for the HLA-A*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 γ/δ T cells, which are not allo-reactive. TCR-transfected γ/δ T cells secreted low quantities of cytokines after antigen-specific stimulation, which were increased dramatically after co-transfection of CD8α-encoding mRNA. In direct comparison with TCR-transfected α/β T cells, TCR-CD8α-co-transfected γ/δ T cells produced more tumor necrosis factor (TNF), and lysed peptide-loaded target cells as efficiently. Most importantly, TCR-transfected α/β T cells and TCR-CD8α-co-transfected γ/δ T cells efficiently lysed adenovirus-infected target cells. We show here, for the first time, that not only α/β T cells but also γ/δ 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.

• Authors: Jan Dörrie, Christian Krug, Christian Hofmann, Ina Müller, Verena Wellner, Ilka Knippertz, Stephan Schierer, Simone Thomas, Elke Zipperer, Dieter Printz, Gerhard Fritsch, Gerold Schuler, Niels Schaft, Rene Geyeregger
• Journal: PloS one (PLoS One) Vol. 9 Issue 10 Pg. e109944 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25289687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Viral
• CD8 Antigens
• CD8alpha antigen
• Cytokines
• Peptides
• Receptors, Antigen, T-Cell, alpha-beta
• Receptors, Antigen, T-Cell, gamma-delta
• RNA

Topics

• Adenoviridae Infections (etiology, immunology, prevention & control)
• Adenoviruses, Human (immunology)
• Amino Acid Sequence
• Antigens, Viral (chemistry, genetics, immunology)
• CD8 Antigens (chemistry, genetics, immunology)
• CD8-Positive T-Lymphocytes (drug effects, immunology, virology)
• Cloning, Molecular
• Cytokines (biosynthesis, metabolism)
• Cytotoxicity, Immunologic
• Electroporation
• Gene Expression
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Jurkat Cells
• Molecular Sequence Data
• Peptides (chemistry, genetics, immunology, pharmacology)
• Primary Cell Culture
• RNA (genetics, immunology)
• Receptors, Antigen, T-Cell, alpha-beta (chemistry, genetics, immunology)
• Receptors, Antigen, T-Cell, gamma-delta (chemistry, genetics, immunology)
• Transfection
• Transplantation, Homologous
• Unrelated Donors