Dendritic cells (DC) are potent antigen presenting cells which link the adaptive and innate arms of the immune response. This normal functioning of DC is attenuated after sepsis when an extended period of immunosuppression affects the phenotype and functions of DC, resulting in a higher risk of secondary infections in the patients. Aiming to understand DC suppression following sepsis, we injected mice intravenously with a low, intermediate and high dose (2.3, 7 and 20 nmol) of CpG which is a mimic for bacterial DNA, and analysed DC function and phenotype one or five days later. At day 1, splenic DC showed phenotypic maturation and impaired antigen presentation, regardless of the CpG dose. The DC cytokine response to different doses of CpG was different though, where the higher doses caused reduced production of pro-Th1 but increased levels of pro-Th2 cytokines compared to the low dose. Subsequently, low dose of CpG did not lead to impairments in the antigen presentation at 5 days while the higher doses did. Since the splenic DC have a half-life of ~ three days, we hypothesize that following the injection of high doses CpG, the spleen cytokine environment “trains” new bone-marrow derived DC to develop functional impairments and phenotypic alterations, which collectively we call “DC paralysis”. Given that in addition to the cytokines produced by DC, the cytokine profile in the mice sera might also affect DC paralysis, I will present recent studies aimed at identifying the cytokines responsible for the establishment of the paralysis program. Ultimately, our goal is to devise strategies to prevent or reduce DC paralysis in critically-ill patients by blocking the cytokine signals that initiate this immunosuppressive program.