Dendritic cells (DC) are potent antigen presenting cells which link the innate and adaptive arms of the immune response. Our team had previously shown that DC function is impaired following severe pulmonary infection contributing to immunosuppression and greater risk of secondary infections in patients. Here, we used mouse models of sepsis and severe trauma and showed they share characteristics of systemic inflammatory response syndrome (SIRS). We showed that a suppressive microenvironment after resolution of SIRS imprints long-term transcriptional and phenotypic alterations on DC, leading to DC dysfunction that consequently impairs priming of T cell responses against subsequent infections. We have been able to propose diagnostic biomarkers and therapeutic solutions towards identifying- and improving the function of- these dysfunctional DC. Indeed, our findings suggest immunostimulatory approaches such as cytokines supplementation in order to improve DC function and boost immune responses in patients that have already experienced (and phased out) SIRS. That offers important implications in managing secondary infections in critically-ill sepsis (including COVID-19) and trauma patients helping to reduce morbidity and mortality rates in patients.