title: Distinct effects of saracatinib on memory CD8+ T cell differentiation.
abstract: Immunologic 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 CD62L(high)/CD44(high) central memory CD8(+) T cells and IFN-γ production but suppressed 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.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari
authors.forename: Benedetto
authors.initials: B
authors.lastname: Farsaci
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: John W
authors.initials: JW
authors.lastname: Greiner
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000187:drug effects* / Q000235:genetics; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007252:Influenza Vaccines / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019041:L-Selectin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000956:Antigens, Viral; D052117:Benzodioxoles; D019496:Cancer Vaccines; C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D007252:Influenza Vaccines; D011799:Quinazolines; D014764:Viral Proteins; D019041:L-Selectin; D007371:Interferon-gamma; C515233:saracatinib; D019061:src-Family Kinases