title: Human CD8+ memory and EBV-specific T cells show low alloreactivity in vitro and in CD34+ stem cell-engrafted NOD/SCID/IL-2Rγc null mice.
abstract: Current strategies in cellular immunotherapy of cancer and viral infections include the adoptive transfer of T cell receptor (TCR) and chimeric antigen receptor engineered T cells. When using transient RNA expression systems in clinical studies, multiple infusions with receptor-redirected T cells appear necessary. However, in allogeneic hematopoietic stem-cell transplantation, repeated transfer of donor-derived T cells increases the risk of alloreactive graft-versus-host disease. We investigated naive-derived (TN), memory-derived (TM), and Epstein Barr virus-specific (TEBV) CD8(+) T cell subsets for alloreactivity upon redirection with RNA encoding a cytomegalovirus-specific model TCR. We observed that alloreactivity to human leukocyte antigen (HLA)-mismatched hematopoietic cells developed at much stronger levels in TN compared with TM or TEBV populations in cytokine-release and cytotoxicity assays. Cytomegalovirus-specific effector function was higher in TCR-transfected TEBV and TM over TN cells. To measure alloreactivity in vivo, we reconstituted NOD/SCID/IL-2Rγc(null) mice with human CD34(+) stem cells and adoptively transferred them with CD8(+) T cell subsets previously stimulated against cells of the HLA-mismatched stem-cell donor. TN cells showed a significant ability to eliminate CD34-derived hematopoietic cells, which was not found with TM and TEBV cells. This reduced alloreactive potential along with strong effector function upon receptor RNA engineering makes CD8(+) memory and EBV-specific T cells advantageous tools in adoptive immunotherapy after allogeneic transplantation.
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany. Electronic address: simone.thomas@ukr.de.
authors.forename: Simone
authors.initials: S
authors.lastname: Thomas
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Klobuch
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Sommer
authors.affiliation: Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Reyn
authors.initials: R
authors.lastname: van Ewijk
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Theobald
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Ralf G
authors.initials: RG
authors.lastname: Meyer
authors.affiliation: Department of Medicine III, Hematology, Internal Oncology and Pneumology, University Medical Center of Johannes Gutenberg University, Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Herr
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006650:Histocompatibility Testing; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D053631:Interleukin Receptor Common gamma Subunit / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D018952:Antigens, CD34; C507941:IL2RG protein, human; D053631:Interleukin Receptor Common gamma Subunit