1. Human adenovirus-specific γ/δ and CD8+ T cells generated by T-cell receptor transfection to treat adenovirus infection after allogeneic stem cell transplantation.
- Author
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Dörrie J, Krug C, Hofmann C, Müller I, Wellner V, Knippertz I, Schierer S, Thomas S, Zipperer E, Printz D, Fritsch G, Schuler G, Schaft N, and Geyeregger R
- Subjects
- Adenoviridae Infections etiology, Adenoviridae Infections immunology, Amino Acid Sequence, Antigens, Viral chemistry, Antigens, Viral genetics, CD8 Antigens chemistry, CD8 Antigens genetics, CD8 Antigens immunology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes virology, Cloning, Molecular, Cytokines biosynthesis, Cytokines metabolism, Cytotoxicity, Immunologic, Electroporation, Gene Expression, Humans, Jurkat Cells, Molecular Sequence Data, Peptides chemistry, Peptides genetics, Peptides immunology, Peptides pharmacology, Primary Cell Culture, RNA genetics, RNA immunology, Receptors, Antigen, T-Cell, alpha-beta chemistry, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta immunology, Receptors, Antigen, T-Cell, gamma-delta chemistry, Receptors, Antigen, T-Cell, gamma-delta genetics, Transfection, Transplantation, Homologous, Unrelated Donors, Adenoviridae Infections prevention & control, Adenoviruses, Human immunology, Antigens, Viral immunology, CD8-Positive T-Lymphocytes immunology, Hematopoietic Stem Cell Transplantation adverse effects, Receptors, Antigen, T-Cell, gamma-delta immunology
- 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.
- Published
- 2014
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