The mammalian immune system displays marked changes in both innate and adaptive immune regulation following severe injury. These injury-induced changes disrupt immune system homeostasis leaving the injured host susceptible to developing infections or excessive inflammatory responses. Advances in our understanding of how injury influences the immune system suggest that severe injury provokes opposing phenotypic effects on cells of the innate and adaptive immune system. This project will test the hypothesis that specific interactions between cells and stimuli of the innate and adaptive immune systems bias the outcome of adaptive immune responses following severe injury. This overall hypothesis will be addressed by the following specific aims: 1. To explore the cellular components underlying the enhanced T-helper 2 (Th2)-type and suppressed Th1-type T-cell response following burn injury. 2. To identify and characterize phenotypic changes in antigen presenting cell types in secondary lymphoid compartments following bum injury and to determine how these changes affect CD4+ T cell activation and differentiation processes. 3. To study the mechanism(s) of action of immunotherapies shown to prevent injury-induced immune dysfunction and to investigate the influences of TLR agonist treatment on antigen-specific CD4+ T cell responses following bum injury. This research program will take advantage of state of the art in vivo approaches to uncover basic mechanisms responsible for altering host immunity following severe injury. An improved understanding of the cellular immune regulatory networks that are modulated following trauma will form the foundation for future research directions addressing this complex scientific and clinically relevant problem. It is hoped that the results of these studies will advance the development of treatments designed to prevent the development of immune system failure and infectious complications following severe injury.