Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors
Résumé
Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.
Mots clés
Animals
Bone Marrow
CD4-Positive T-Lymphocytes
Cell Line
Tumor
Cell Transplantation
Cells
Cultured
Flow Cytometry
Forkhead Transcription Factors
Genetic Therapy
Genetic Vectors
Green Fluorescent Proteins
HEK293 Cells
Humans
Immunotherapy
Adoptive
Lentivirus
Leukocytes
Mononuclear
Luciferases
Mice
Inbred NOD
Knockout
SCID
Spleen
Thymus Gland
Transduction
Genetic
Transplantation
Heterologous