1. Distinct Effects of Saracatinib on Memory CD8+ T Cell Differentiation.
- Author
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Shinji Takai, Sabzevari, Helen, Farsaci, Benedetto, Schlom, Jeffrey, and Greiner, John W.
- Subjects
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CANCER immunotherapy , *CELL differentiation , *IMMUNE response , *T cells , *NUCLEOPROTEINS , *INFLUENZA viruses , *RAPAMYCIN - Abstract
Immunologie memory involving CD8+ T cells is a hallmark of an adaptive Ag-specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T cell response has led to new approaches that target the magnitude and quality of the memory T cell response. In this article, we show that T cells from TCR transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases--priming, expansion, contraction, and memory--of an Ag-specific T cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62Lhigh/CD44high central memory CD8+ T cells and IFN-γ production but sup-pressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8+ T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine [ABSTRACT FROM AUTHOR]
- Published
- 2012
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