Targeted adenovirus-mediated gene delivery to T cells via CD3.

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 interferonγ(IFN-γ), as the delivered gene can continuously produce that interferon. However which immune cell type should optimally express IFN-γis unclear as the phenotypes of both DC and T cells are enhanced by it. Here, we used AAV to compare and contrast IFN-γgene delivery into DC or T cells, and versus the addition of exogenous IFN-γ, for stimulating carcinoembryonic antigen-(CEA-) specific CTL. It was found that AAV/IFN-γdelivery into T cells (autocrine) resulted in T cell populations with the highest CD8(+)/CD4(+) ratio, highest IFN-γ(+)/IL-4(+) ratio, highest CD69(+),CD8(+) levels, and lowest CD4(+)/CD25(+) levels, all consistent with the strongest Th1 response. Most importantly, AAV/IFN-γtransduction 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-γautocrine gene delivery into T cells is worthy of further study towards maximizing the generation of antigen-specific anticancer CTL killers.

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Gene Delivery into Primary T Cells: Overview and Characterization of a Transgenic Model for Efficient Adenoviral Transduction

Immunologic Research ◽

10.1385/ir:26:1-3:131 ◽

2002 ◽

Vol 26 (1-3) ◽

pp. 131-142 ◽

Cited By ~ 10

Author(s):

Vincent Hurez ◽

Robin D Hatton ◽

James Oliver ◽

R James Matthews ◽

Casey T Weaver

Keyword(s):

T Cells ◽

Gene Delivery ◽

Transgenic Model ◽

Adenoviral Transduction

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Type I IFN gene delivery suppresses regulatory T cells within tumors

Cancer Gene Therapy ◽

10.1038/cgt.2014.60 ◽

2014 ◽

Vol 21 (12) ◽

pp. 532-541 ◽

Cited By ~ 16

Author(s):

H Hashimoto ◽

R Ueda ◽

K Narumi ◽

Y Heike ◽

T Yoshida ◽

...

Keyword(s):

T Cells ◽

Gene Delivery ◽

Regulatory T Cells ◽

Type I ◽

Type I Ifn

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Pulmonary Interleukin-23 Gene Delivery Increases Local T-Cell Immunity and Controls Growth of Mycobacterium tuberculosis in the Lungs

Infection and Immunity ◽

10.1128/iai.73.9.5782-5788.2005 ◽

2005 ◽

Vol 73 (9) ◽

pp. 5782-5788 ◽

Cited By ~ 67

Author(s):

Kyle I. Happel ◽

Euan A. Lockhart ◽

Carol M. Mason ◽

Elizabeth Porretta ◽

Elizabeth Keoshkerian ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Gene Delivery ◽

Lymph Nodes ◽

T Cell Immunity ◽

Activated T Cells ◽

Cell Immunity ◽

Ifn Γ ◽

Interleukin 23

ABSTRACT Interleukin-23 (IL-23) is a heterodimeric cytokine that shares IL-12 p40 but contains a unique p19 subunit similar to IL-12 p35. Previous studies indicate a greater importance for intact IL-12/23 p40 expression than IL-12 p35 for immunity against Mycobacterium tuberculosis, suggesting a role for IL-23 in host defense. The effects of IL-23 on the outcome of pulmonary infection with M. tuberculosis have not been described. Here, we show that local delivery of replication-defective adenovirus vectors encoding IL-23 (AdIL-23) greatly stimulated expression of both gamma interferon (IFN-γ) and IL-17 in lung tissues of otherwise normal mice. When given 72 h prior to infection with M. tuberculosis, AdIL-23 significantly reduced the bacterial burden at 14, 21, and 28 days. Markedly lower levels of lung inflammation were observed at 28 days than in control mice pretreated with control adenovirus (AdNull) or vehicle controls. AdIL-23 pretreatment resulted in increased numbers of CD4+ CD25+ activated T cells in lungs and draining lymph nodes compared to control groups and more CD4+ T cells bearing surface memory markers in lung lymph nodes. IL-23 gene delivery also significantly enhanced host anti-mycobacterial T-cell responses, as shown by elevated levels of IFN-γ and IL-17 secreted in vitro following restimulation with M. tuberculosis purified protein derivative. Overall, our data show that transient IL-23 gene delivery in the lung is well tolerated, and they provide the initial demonstration that this factor controls mycobacterial growth while augmenting early pulmonary T-cell immunity.

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