The overall goal of this application is to characterize physiologically relevant factors controlling NK and T cell responses in vivo. The work is based on the investigator's previous analyses of cytokine responses and of NK and T cell activation and proliferation during infections in mice with LCMV or MCMV, and after treatments with the chemical analog of viral nucleic acids, polyinosinic:polycytidylic acid (poly I:C), IFN-alpha/beta, or IL-12. The experiments proposed here will expand characterization by examining the hypothesis that: (I) particular cellular interactions with virus-type stimuli determine composition of innate cytokine, and resulting NK cell, responses; (II) IL-15 is induced by IFN-alpha/beta in vivo to promote NK cell proliferation as well as support conditions preferentially activating CD8 T cell responses; (III) pathways are in place limiting systemic NK cell IFN-gamma production to protect against damaging consequences of this response; (IV) alternative pathways sustain local IFN-gamma production to access beneficial effects; and (V) NK cells can limit CD4 T cell responses through an IFN-alpha/beta- induced pathway. These will be examined in four specific aims to: 1) further characterize regulation of NK cell responses under conditions of challenges with viruses, viral analogs, and IFN-alpha/beta to include potential roles of IL-15, events in the bone marrow, and conditions promoting IL-12 refractory states: 2) define mechanisms for the different pathways of cytokine induction and NK cell activation by examining ranges of cytokines induced in particular cell types as well as initial targets of the in vivo challenge conditions; 3) identify mechanisms regulating NK cell responses in livers during MCMV infections, including defining roles for IGIF (interferon gamma inducing factor), and characterizing responses of NK1+ T cells in this compartment; and 4) determine mechanisms by which innate responses regulate T cell responses, including characterizing IFN-alpha/beta- induced and NK cell-mediated effects. The information resulting from this work will generate basic immunological knowledge as well as significant new insights for developing anti-viral and/or anti-cancer treatment protocols.
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