title: Autocrine, not paracrine, interferon-gamma gene delivery enhances ex vivo antigen-specific cytotoxic T lymphocyte stimulation and killing.
abstract: The adoptive transfer of antigen-specific cytotoxic T lymphocytes (CTL) shows promise in the treatment of cancer and infectious diseases. We utilize adeno-associated virus-(AAV-) based antigen gene-loaded dendritic cells (DCs) to stimulate such antigen-specific CTL. Yet further improvements in CTL stimulation and killing may result by gene delivery of various Th1-response interferons/cytokines, such as interferon gamma (IFN-gamma), as the delivered gene can continuously produce that interferon. However which immune cell type should optimally express IFN-gamma is unclear as the phenotypes of both DC and T cells are enhanced by it. Here, we used AAV to compare and contrast IFN-gamma gene delivery into DC or T cells, and versus the addition of exogenous IFN-gamma, for stimulating carcinoembryonic antigen-(CEA-) specific CTL. It was found that AAV/IFN-gamma delivery into T cells (autocrine) resulted in T cell populations with the highest CD8(+)/CD4(+) ratio, highest IFN-gamma(+)/IL-4(+) ratio, highest CD69(+),CD8(+) levels, and lowest CD4(+)/CD25(+) levels, all consistent with the strongest Th1 response. Most importantly, AAV/IFN-gamma transduction of T cells resulted in antigen-specific T cell populations with the highest killing capabilities, 49% above other treatments. These data strongly suggest that AAV/IFN-gamma autocrine gene delivery into T cells is worthy of further study towards maximizing the generation of antigen-specific anticancer CTL killers.
authors.affiliation: Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Dazhi
authors.initials: D
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.forename: Chang Xuan
authors.initials: CX
authors.lastname: You
authors.forename: Maohua
authors.initials: M
authors.lastname: Cao
authors.forename: Rong Cheng
authors.initials: RC
authors.lastname: Luo
authors.forename: Paul L
authors.initials: PL
authors.lastname: Hermonat
mesh_terms: D002272:Carcinoembryonic Antigen / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D000229:Dependovirus / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000276:immunology; D008213:Lymphocyte Activation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016662:Virus Integration
chemical_list: D002272:Carcinoembryonic Antigen; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007371:Interferon-gamma