PROJECT SUMMARY Traumatic injuries disrupt immune system homeostasis, which can predispose patients to opportunistic infections and other trauma-associated complications like systemic inflammatory response syndrome (SIRS), organ damage, and chronic critical illnesses. Trauma induces unique and complex host responses that are initiated by tissue damage and the release of danger-associated molecular patterns (DAMPs) that trigger specific immune reactions. We identified that a subset of CD4+ T cells called regulatory T cells (Tregs) are acutely activated by injury in a mouse burn trauma model. The counter-inflammatory suppressive activity of Tregs is enhanced by trauma, which suggests that Tregs may control the intensity of post-trauma inflammation and restoration of immune system homeostasis. People can have different numbers of Tregs in their tissues or have different functional Treg responses to trauma that could determine trajectory of their response to traumatic injuries. Our hypothesis is that Tregs control immune reactions to DAMPs and influence the trajectory of the host response to trauma. To address this hypothesis, we propose a series of trauma immunology studies to systematically interrogate; 1) Treg control of immune system phenotypes and homeostasis, 2) trauma-induced Treg activation mechanisms, and 3) effects of modulating Tregs on immune phenotypes, anti-microbial immune function, and the two-hit SIRS response. The specific aims for this project are; 1) To determine how CD4+ Tregs control immune system reactivity to trauma, 2) To define the specificity and molecular nature of trauma-reactive CD4+ Tregs and other T cells, 3) To investigate how CD4+ Tregs influence anti-microbial immunity and two-hit SIRS. We anticipate that the outcome of this research will significantly advance our fundamental knowledge of specific immune mechanisms that modulate trauma immunity. We have several significant goals that we wish to achieve during the course of this project; 1) to provide new insights into the biology of Treg activation and function, 2) to develop a deeper understanding of immune system control of the mammalian trauma response, and 3) to explore the therapeutic potential of modulating Treg activation and function as a specific trauma immunotherapy to improve immune function and balance following trauma.