Abstract
Gene therapy with recombinant viral vectors such as adenovirus and adenovirus-associated virus holds great promise in treating a wide range of diseases because of the high efficiency with which the viruses transfer their genomes into host cells in vivo. However, the activation of the host immune responses remains a major hurdle to successful gene therapy. Studies in the past two decades have elucidated the important role co-stimulation plays in the activation of both T and B cells. This review summarizes our current understanding of T cell co-stimulatory pathways, and strategies targeting these co-stimulatory pathways in gene therapy applications as well as potential future directions.
Highlights
Virus-based vectors such as adenovirus and adenovirus-associated virus (AAV) have been widely used in gene therapy applications due to their high efficiency of transduction into a variety of cells in vivo
The original two-signal hypothesis (Lafferty et al, 1974, 1980) proposes that full T cell activation requires two signals: antigenspecific T cell recognition provided by the engagement of the TCR–CD3 complex with a processed antigenic peptide bound to the major histocompatibility complex (MHC) molecule on the surface of an antigen presenting cell (APC), and an antigen-non-specific co-stimulatory signal provided by the interactions between cell surface molecules on the APC and the T cell
CD28/B7-mediated signaling upregulates the expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) which effectively competes with CD28 for B7-1/B7-2 at later stages of the immune response to counter T cell activation, suggesting a mechanism for achieving balance between positive and negative stimulation
Summary
Virus-based vectors such as adenovirus and adenovirus-associated virus (AAV) have been widely used in gene therapy applications due to their high efficiency of transduction into a variety of cells in vivo. CD28/B7-mediated signaling upregulates the expression of CTLA-4 which effectively competes with CD28 for B7-1/B7-2 at later stages of the immune response to counter T cell activation, suggesting a mechanism for achieving balance between positive and negative stimulation.
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