Consequences of Stable Transduction and Antigen-Inducible Expression of the Human Interleukin-7 Gene on Tetanus-Toxoid-Specific T Cells

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Abstract
Interleukin-7 (IL-7) has previously been shown to increase antigen-specific immune responses; the effect of IL-7 on human antigen-specific T cell lines has not directly been addressed. A tetanus-toxoid (TT)-specific T cell line exhibited increased proliferation in the presence of exogenous IL-7, suggesting that IL-7 may be useful in the potentiation of immune responses to defined microbial antigens. Murine retroviral vectors encoding the human IL-7 gene and the neomycin phosphotransferase gene (neoR) were packaged into murine retroviral particles, and supernatants containing these retroviral vectors were used to infect a CD4+ lymphoblastoid cell line. Stable integration of the retroviral vector and constitutive expression of the IL-7 gene were observed. Successful IL-7 gene transduction into TT-specific T cells was also accomplished. Detection of neoR DNA sequences and expression of IL-7-specific mRNA increased with selection in geneticin. Production of IL-7 in these cells was induced by exposure to TT. Production of IL-4, IL-6, and interferon-γ (IFN-γ) was detected after antigenic stimulation; there was, however, no effect of IL-7 on the pattern or kinetics of cytokine production by these cells. Human IL-7 transduced cells showed greater proliferation to TT than control T cells, particularly at subthreshold TT concentrations. These data imply that genetic modification of antigen-specific T cells may be a plausible strategy for the study and manipulation of the immune responses to microbial pathogens. The systemic administration of cytokines to augment immune responses to viral and malignant processes is associated with severe, even fatal, toxicity. The use of genetic transfer to achieve expression of nontranscribed cytokine genes in antigen-specific T cells might augment immune responses with minimal, incidental toxicity. Exogenous IL-7, a cytokine with effects on both cellular and humoral immune responses, boosted specific T cell proliferative responses to TT. Interestingly, the IL-7 effect was most pronounced at suboptimal antigen concentrations. Transduction of these normal T cell lines with a retroviral vector containing the human IL-7 gene resulted in the production of IL-7 in an antigen-dependent manner. Transduction of the IL-7 gene was functionally associated with increased proliferation to TT, suggesting that the modification of antigen-specific cells with cytokine genes may selectively improve immune responses to viral and bacterial pathogens.