title: TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis.
abstract: CD8(+) T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8(+) T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8(+) T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8(+) T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8(+) T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands m.wolkers@sanquin.nl f.salerno@sanquin.nl.
authors.forename: Fiamma
authors.initials: F
authors.lastname: Salerno
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands.
authors.forename: Aurelie
authors.initials: A
authors.lastname: Guislain
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands.
authors.forename: Dilay
authors.initials: D
authors.lastname: Cansever
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands.
authors.forename: Monika C
authors.initials: MC
authors.lastname: Wolkers
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D006019:Glycolysis; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008262:Macrophage Activation; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012119:Respiration; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines; D007371:Interferon-gamma; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; C493486:Tlr2 protein, mouse; C477038:Tlr7 protein, mouse; C421683:Pik3cd protein, mouse