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Xu J , Lee MH , Chakhtoura M , Green BL , Kotredes KP , Chain RW , Sriram U , Gamero AM , Gallucci S
STAT2 Is Required for TLR-Induced Murine Dendritic Cell Activation and Cross-Presentation
J Immunol. 2016 Jul 01;197(1) :326-36
PMID: 27233962    PMCID: PMC4912940   
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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-alpha 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-alpha 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-alpha, 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.
Notes
1550-6606 Xu, Jun Lee, Michael H Chakhtoura, Marita Green, Benjamin L Kotredes, Kevin P Chain, Robert W ORCID: http://orcid.org/0000-0001-9509-1010 Sriram, Uma Gamero, Ana M ORCID: http://orcid.org/0000-0001-7843-1415 Gallucci, Stefania ORCID: http://orcid.org/0000-0003-4737-8003 P30 CA006927/CA/NCI NIH HHS/United States R01 AI076423/AI/NIAID NIH HHS/United States Journal Article United States J Immunol. 2016 Jul 1;197(1):326-36. doi: 10.4049/jimmunol.1500152. Epub 2016 May 27.