STAT2 is required for TLR-induced murine dendritic cell activation and cross-presentation

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 IFNstimulated genes. The cDC responses to exogenous IFN-a 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, LPSinduced production of IL-12 was STAT2 and type I IFN receptor (IFNAR) dependent, whereas LPS-induced production of TNF-a 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-a, 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.