Our laboratory works on two different topics: innate immunity and inflammation. Our focus on innate immunity is centered on the study of antigen cross-presentation mechanisms and the immunobiology of dendritic cells. Effective immune responses against tumor antigens that are not endogenously expressed by dendritic cells (DCs) and against viruses that do not infect antigen presenting cells (APCs) require extracellular antigens to stimulate CD8+ T cells via the MHC I pathway through a process poorly characterized at the molecular level known as antigen cross-presentation. We are using a series of systematic genetic approaches to identify the molecular machinery involved in antigen cross-presentation. In addition, we want to explore antigen cross-presentation as an early immune-regulatory checkpoint in the control of CD8+ T cell priming by dendritic cells, to find drugs that inhibit negative regulators of this process, as they are likely to improve the generation of effective T cells responses against tumors and are good candidates for novel adjuvant therapies for cancer treatment. Our second, and currently dominating theme of the laboratory, relates to inflammation. Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options outside of infection control and organ support measures. Based on our recent discovery in mice showing that anthracycline drugs prevent organ failure without affecting the bacterial burden in a model of severe sepsis, we propose that strategies aimed at target organ protection have extraordinary potential for the treatment of sepsis and possibly for other inflammation-driven conditions. However, the mechanisms of organ protection and disease tolerance are either unknown or poorly characterized. The central goal of this research program is to identify and characterize novel cytoprotective mechanisms, with a focus on DNA damage response dependent protection activated by anthracyclines as a window into stress-induced genetic programs leading to tissue protection.