Dendritic cells (DCs) serve as a key component of innate immunity and bridge innate and adaptive immune responses against to bacteria and other pathogens. Many immune disorders are thought to be a consequence of out-of-control of inflammatory response to bacterial toxins, such as sepsis is a result of excessive inflammation with a suppression of adaptive immunity post-sepsis. Therefore, manipulating the function of DC in innate immune response without affecting its capability to initiate adaptive immunity could be a novel therapeutic approach for treatment of sepsis. Using an inducible Jak2 deficiency model, here we have demonstrated that Jak2 could be a perfect target to solely suppress DC's capacity in innate immune response. Other than its functionality in DC development, Jak2 also plays a pivotal role in modulation of innate immune response. DCs deficient for Jak2 display an immature phenotype characterized by low expression of MHC-II and costimulatory molecules and a reduced secretion of pro-inflammatory cytokines upon stimulation. However, their capability to initiate adaptive immune response was not impaired. As a result, mice deficient for Jak2 are resistant to LPS-induced septic shock. Our studies further revealed that Jak2/SATA5 signaling is implicated in DC development, while Jak2/STAT6 signaling is responsible for the regulation of pro-inflammatory cytokine secretion in DCs.