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 systemic inflammation when an extended period of immunosuppression causes DC apoptosis and dysfunction (called “DC paralysis”), resulting in greater risk of secondary infections and higher rates of mortality and morbidity in patients. Aiming to characterise DC paralysis, mice were injected intravenously with CpG (a mimic for bacterial DNA). It led to a transient systemic inflammation followed by three weeks of impairments in antigen-specific T cell responses in the mice spleen. Use of CD11c-mOVA mice showed that DC are responsible for these impairments, but purified DC loaded with antigen in vitro could prime T cells normally. ex vivo antigen presentation was tested to address this discordance, and confirmed on the role of spleen microenvironment in “training” the DC paralysed. With prospects of silencing this environmental suppression and thus restoring the DC function, blocking of cytokines signalling including those of interleukin (IL)-4, IL-10, IL-33 or interferon a/b were tested in vivo, via antibody neutralisation or use of knock out mice. Transcriptomics of paralysed DC also showed the likely involvement of the three former cytokines in a shared regulatory pathway with transcription factor peroxisome proliferator-activated receptor gamma (PPAR-g) being a likely “master regulator” for paralysis program. Together, we conclude that systemic inflammation triggers “extrinsic signals” from microenvironment and “intrinsic signals” in DC, which contribute to DC paralysis in a mutually inclusive manner. Further investigations are ongoing to better understand and harness these molecules and signals in this mouse model of DC paralysis. Ultimately, we aim to diagnose or ameliorate DC paralysis in critically-ill patients by use of PPAR-g as a potential biomarker or blocking the respective cytokines signalling.