Severe injury triggers a state of immune suppression that predisposes the injured patient to infection and sepsis. Traumatic injury alters the cytokine-producing phenotype of T cells from injured patients and experimentally injured animals. Studies by the applicant have demonstrated that therapy with cytokines or cytokine antagonists that correct burn injury-induced effects on T cells can protect mice from developing immune suppression. The mechanistic basis for injury-induced effects on T cell mediated immune responses remains poorly understood. The applicant proposes to use a state of the art approach to examine the in vivo mechanisms responsible for injury-induced effects on T cells. The hypothesis to be tested in these studies is that severe injury alters antigen-specific T cell activation, that naive T cells are affected differently than antigen activated T cells and that T cell costimulatory pathways are important in mediating these effects. The proposed project will utilize T cell receptor transgenic mice as an experimental tool to dissect the effect of injury on T cell activation, differentiation, and deletion or expansion in vivo.
Three specific aims are proposed: 1) to determine the effect of burn injury on naive and antigen-activated T cells in vivo; 2) to define the kinetics of burn injury effects on T cells in vivo; and, 3) to test the hypothesis that T cell costimulation contributes to the injury-induced effects on T cells. The results of the proposed experiments should provide needed insight into mechanisms responsible for injury-induced effects on the adaptive immune system. The results may also contribute new information leading to the development of novel therapeutic approaches for preventing injury-induced immune dysfunction.
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