title: STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation.
abstract: TLR-stimulated cross-presentation by conventional dendritic cells (cDCs) is important in host defense and antitumor immunity. We recently reported that cDCs lacking the type I IFN signaling molecule STAT2 are impaired in cross-presenting tumor Ags to CD8(+) T cells. To investigate how STAT2 affects cross-presentation, we determined its requirements for dendritic cell activation. In this study, we report that STAT2 is essential for the activation of murine female cDCs upon TLR3, -4, -7, and -9 stimulation. In response to various TLR ligands, Stat2(-/-) cDCs displayed reduced expression of costimulatory molecules and type I IFN-stimulated genes. The cDC responses to exogenous IFN-α that we evaluated required STAT2 activation, indicating that the canonical STAT1-STAT2 heterodimers are the primary signaling transducers of type I IFNs in cDCs. Interestingly, LPS-induced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-α and IL-6 was STAT2 and IFNAR independent, suggesting a specific role of the IFNAR-STAT2 axis in the stimulation of proinflammatory cytokines by LPS in cDCs. In contrast, R848- and CpG-induced cytokine production was less influenced by the IFNAR-STAT2 axis. Short kinetics and IFNAR blockade studies showed that STAT2 main function is to transduce signals triggered by autocrine type I IFNs. Importantly, Stat2(-/-) cDCs were deficient in cross-presenting to CD8(+) T cells in vitro upon IFN-α, CpG, and LPS stimulation, and also in cross-priming and licensing cytotoxic T cell killers in vivo. We conclude that STAT2 plays a critical role in TLR-induced dendritic cell activation and cross-presentation, and thus is vital in host defense.
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
authors.forename: Marita
authors.initials: M
authors.lastname: Chakhtoura
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Green
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Kotredes
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140;
authors.forename: Robert W
authors.identifier: 0000-0001-9509-1010
authors.initials: RW
authors.lastname: Chain
authors.affiliation: Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140.
authors.forename: Uma
authors.initials: U
authors.lastname: Sriram
authors.affiliation: Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; and.
authors.forename: Ana M
authors.identifier: 0000-0001-7843-1415
authors.initials: AM
authors.lastname: Gamero
authors.affiliation: Laboratory of Dendritic Cell Biology, Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140; gallucci@temple.edu.
authors.forename: Stefania
authors.identifier: 0000-0003-4737-8003
authors.initials: S
authors.lastname: Gallucci
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D045142:Cross-Priming; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology*; D007109:Immunity; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; C508032:Ifnar1 protein, mouse; D050795:STAT2 Transcription Factor; C494085:Stat2 protein, mouse; D053633:Receptor, Interferon alpha-beta