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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Immunity and Host Defense Study Section (IHD)
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Miller, Lara R
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Brown University
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