Sepsis and multiple organ dysfunction syndrome (MODS) after trauma are a leading cause of mortality and morbidity. Post injury! lymphocyte immune paralysis, apoptosis, and loss of dendritic cell antigen presenta- tion and costimulation are associated with development of sepsis and MODS. T cell dysfunctions were thought to result solely from failure to fully activate through costimulatory surface receptors/ligands leading to apoptosis and T cell tolerance. However, T cell co-repressor receptor/ligands have been recently shown to counterbalance and overwhelm costimulator activation by inducing inhibitory signal transduction molecules which degrade and dephosphorylate the activating signal proteins. These co-repressors bidirectionally trig- ger apoptosis and tolerance in both the DC and T cells. Our global hypothesis is that this bidirectional co- repressor receptor/ligand triggering is responsible for post injury T cell paralysis and DC dysfunction. The co- repressor expressing anergic T cells induce paralysis in naive T cells and costimulation dysfunctions in DC. We further postulate that in concert with the co-repressor receptors, trauma mediators uniquely upregulate and trigger additional negative T cell signaling by increasing inflammation sensitive co-repressor receptor expression and triggering. To test these hypotheses we proposed 2 Specific Aims: First, to define how T cell costimulatory or co-repressor receptor expression and activating vs. inhibitory signaling pathways are altered when costimulation deficient and co-repressor tolerance are combined by (1) characterizing a human anergic T cell model and by comparing this model to alterations in refractory anergic patient T cells. Second, to as- sess if mechanisms by which trauma patients'refractory anergic and/or apoptotic T cells perpetuate post in- jury immunosuppression include 1) Apoptotic T cells'altering DC costimulation/co-repressor receptor/ligand balance to induce tolerizing DC and/or DC apoptosis. 2) Patients'refractory anergic T cells inducing co- repressor dominant tolerizing DC or DC apoptosis. 3) Patients'refractory anergic T cells inducing co- repressor dominance and/or elevate inhibitory signal transduction pathways in naive or activated T cells. Identification of T cell co-repressor receptors which trigger post trauma T cell refractory anergy may indicate targets for interventional biochemical and/or biological manipulation of injury induced aberrant T cell activa- tion representing a new therapeutic strategy for treating post injury sepsis and MODS.
