A lingering conundrum of the immune response is how do certain immune/inflammatory cells remember whether or not they should be actively transcribing specific genes, which would facilitate their participation in a given inflammatory response. Our laboratory is investigating novel epigenetic changes, induced via post- translational modifications of histones, as mechanisms to regulate the expression profiles of immune cell derived mediators. Using both normal and septic human cell-based systems and an experimental model of infectious polymicrobial peritonitis-induced sepsis, we have begun to address the epigenetic based mechanisms that may lead to down-stream sepsis-associated complications. We present data that T cell function is directly dependent upon robust participation of epigenetic-based enzymes; setting chromatin modifications that result in transcriptional activation. When this system goes awry, as we have identified in life-threatening sepsis, a state of immune-suppression results. We present novel evidence demonstrating that cytokines, known to activate and differentiate specific T cell subsets, do so by controlling the expression of epigenetic-based chromatin remodeling enzymes. Importantly, our preliminary data reveals that in both an experimental model of sepsis and in documented septic patients these same epigenetic pathway is impaired leading to a significant reduction in T cell activation and proliferation. We hypothesize that IL-12/STAT4-dependent differentiation of nave T cells to IFN-? expressing Th1 cells is mechanistically controlled by the chromatin modifying lysine methyltransferase, mixed lineage leukemia, MLL1, and is impaired during severe sepsis. This hypothesis will be investigated via the following specific aims: 1) 1) To identify the IL12 driven, epigenetic dependent mechanism(s) mediated by the lysine methyltransferase MLL1, responsible for the normal differentiation, proliferation, and IFN-? production by Th-1 cells; 2) To determine if the impairment of T cell differentiation and reduced IFN-? production found in post-septic Th1 cells is mechanistically dependent on aberrant MLL1 expression/function; 3) To translationally investigate the IL-12 dependent Th-1 cell differentiation pathway in human post-septic T cells obtained during the course of a 1 year clinical follow up to sepsis by evaluating MLL1 expression, IFN-? production, proliferative capacity of T cells and correlating these results with defined clinical parameters.
of our proposed studies is to demonstrate that the inflammatory cytokine environment directs the epigenetic-dependent molecular mechanisms which subsequently influences the activation events of immune cells and influences what inflammatory mediators they produce. This information is important as we have identified that the events which lead to the activation of a population of immune cells known as T cells is impair during severe sepsis and results in the immunosuppression and susceptibility of septic patients to pneumonia. We also believe that this impair T cell activation mechanism is responsible for the impair immune response associated with septic patients long after they have 'recovered' from this life threatening event. We believe the data generated from these studies will provide a potential avenue for the development of new biomarkers and novel, efficacious therapies for survivors of severe sepsis.
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