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Natural Killer T cells and the immune response to injury

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Immune dysfunction that occurs subsequent to severe burn injury continues to be a major obstacle in the prevention of infectious complications; the major contributing factors to morbidity and mortality after burn injury. While a significant amount of research has been done on the roles of conventional T cells, B cells, granulocytes, and macrophages in the immune response to injury, a possible role for lesser known cell types, such as natural killer T (NKT) cells, has not been described. NKT cells have recently emerged as powerful immunoregulatory cells that influence the effector functions of T cells through their ability to rapidly secrete large amounts of immunomodulatory cytokines such as interleukins (IL)-4, 10, and 13, as well as interferon gamma (IFNgamma) subsequent to stimulation of their invariant T cell receptor via the CD1d molecules expressed on conventional antigen presenting cells (APCs). Preliminary studies presented here used a mouse model of burn injury to demonstrate that 24 hours after bum injury, the effector phase of antigen specific immunity is significantly suppressed, indicated by decreased delayed type hypersensitivity (DTH) responses, decreased in vitro T cell proliferation in response to recall exposure to antigen, decreased IFNgamma production, and an increase in IL-4 production. Here we present the novel findings that blockade of NKT cell activation by treatment of mice with anti-CD1d mAb significantly prevents the injury-associated decreases in DTH and T cell proliferation, and prevents the injury-induced increase in IL-4 production. Similar findings were observed in experiments that used mice deficient of the CD1d molecule. While several cell types can produce IL-4, we observed NKT cells to be the only source of this immunosuppressive cytokine in the early stages after injury. From these pieces of evidence, we hypothesized that NKT cells contribute to injury-associated immune dysfunction through the rapid release of immunomodulatory cytokines known to actively suppress effector T cell function. In Aim 1 of the proposal, we will confirm a role for CD1d stimulation of NKT cells by comparing immune responses (DTH, proliferation, cytokine production) in sham vs. burn-injured NKT cell deficient Jalphat281-/- and CD1d+ mice before and after reconstitution with normal NKT cells and CDld+ APCs. In the Aim 2, we will use a fluorescent tetramer labeling method combined with FACS sorting to isolate NKT cells after sham vs. burn injury and compare their cytokine production profiles by real-time PCR and ELISPOT. To confirm whether NKT cell-derived cytokines are crucial to injury-associated immune suppression, we will reconstitute sham vs. burn-injured mice with NKT cells isolated from particular cytokine knockout mice. Additionally, we will determine whether NKT cell-derived cytokines act directly on effector T cells. In Aim 3, we will examine whether APCs from sham vs. bum-injured mice differentially modulate NKT cell cytokine production in vitro and identify the molecular mechanism(s) by which the differential regulation may occur. Lastly, in Aim 4, we will use the NKT cell-specific ligand, alpha-galactosylceramide, known to promote NKT-dependent protective immunity, as a pharmacological approach to restore immune function after burn injury. Such studies will provide valuable insight into the role of NKT cells in the immune response to injury and may provide a new perspective for the development of therapeutic intervention for immune suppression among bum patients.
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