Impaired host responses after trauma or surgery (traumatic stress) render patients susceptible to sepsis thus greatly increasing morbidity, mortality and cost. T cell dysfunction is central to impaired host defenses after traumatic stress and is characterized by decreased proliferation, and production of cytokines (Interleukin 2 and interferon gamma) and a decrease in the number of T cell receptors (TCR) expressed on the cell membrane as a result of decreased L, chain. Myeloid cells are known to cause T cell dysfunction in traumatic stress, but the nature of these cells and how they cause T cell dysfunction is unclear. Our laboratory has recently found that traumatic stress induces the activation of a distinct immature myeloid cell population expressing both CD1 lb+ and GR1+ markers. These cells infiltrate the marginal zones of the spleen within 6 hours after trauma and by 12 hours constitute up to 15% of all spleen cells. Trauma-induced immature myeloid GDI lb+/GR-l+ cells (TIIMC) decrease T cell proliferation, impair cytokine production and decrease TCR zeta, chain expression. TIIMC also express very high levels of arginase 1 (ARG1) and possibly the cationic aminoacid transporter Cat2b and therefore appear to deplete arginine, an amino acid necessary for T cell function. Based on these observations we hypothesize that traumatic stress generates specific signals which induce arginase 1 expression in a distinct immature myeloid cell population that can alter T-cell function through arginine depletion. Our goals are to determine the mechanisms by which ARG1 in TIIMC causes T cell dysfunction, to identify the signals that induce and sustain the production of ARG1 in TIMC and to develop strategies designed to block or overcome T cell dysfunction after traumatic stress. We will answer these questions using a highly reproducible model of traumatic stress, in which ARG1 production is proportional to the severity of injury. We believe that the identification of an immature myeloid cell in a murine model of trauma is a novel observation that will allow us to understand T cell dysfunction in trauma and evaluate therapeutic strategies with translational potential.
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