Natural killer T cells are a unique subset of T lymphocytes that rapidly produce Th1 and Th2 cytokines, most notably IFN-y and IL-4. NK T cells are CD4+CD8"""""""" or double negative and are dependent on a non-classical, non-polymorphic MHC class l-like molecule, CD1d, for positive selection, antigen presentation, and activation. Using the synthetic ligand, a-galactosylceramide (a- GalCer), we found that optimal NK T cell activation of NK cells requires a functional IFN-y signaling. The cross-talk between NK T cells and NK cells is indirect and mediated by macrophages and dendritic cells. To determine whether a cross-talk between NK T cells and NK cells occurs during a physiological stimulus, we used the murine cytomegalovirus (MCMV). This virus replicates in the murine liver, an organ particularly rich in NK cells and NK T cells as well as being characterized by high CD1d expression on hepatocytes. Upon MCMV infection, we have shown that NK T cells sense viral infection prior to NK cells in a STAT1 dependent manner and subsequently expand and synthesize cytokines. This early activation of NK T cells has an impact on the quality of both the innate and adaptive immune responses to the infection. Importantly, we found that the CD8+ T cell response to MCMV is impaired in NK T cell deficient animals. We therefore propose in the first Specific Aim to define the molecular and cellular mechanisms that lead to NK T cell activation of NK cells. In the second Aim, we propose to determine the NK T cell contribution to the innate and adaptive immune response to MCMV infection. In the third Aim, we propose to define a-GalCer adjuvant properties and to examine its long-term effects on NK T cell status in the context of a physiological stimulus. We believe that NK T cell activation has profound consequences in shaping both the innate and the adaptive immune response to pathogens. The novel studies proposed here will provide insight into the role of NK T cells during viral infection and may provide strategies for the manipulation of this important category of immune cell responses.
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