Natural killer cells (NK) have originally been defined as mediators of spontaneous cytotoxicity against virus-infected and tumor cells. In human peripheral blood the majority of NK cells can mediate cell lysis via perforin. Our preliminary data show that the majority of NK cells in human secondary lymphoid organs are immunoregulatory by secreting cytokines immediately after activation. Within one week after activation they, in addition, mature to the phenotype of peripheral blood cytotoxic NK cells and probably leave the secondary lymphoid tissues. Dendritic cells (DCs) are the primary antigen presenting cells that initiate adaptive immunity and we as well as other groups have recently demonstrated that DCs activate peripheral blood NK cells efficiently. Since DCs home rapidly to secondary lymphoid organs upon maturation and our preliminary data demonstrate that they activate NK cells in these tissues, we propose that DCs are the principal mediators of NK activation prior to T cell responses. In addition, we propose that secondary lymphoid tissues are the main site of this early NK activation. Early NK activation has been shown crucial in limiting viremia and tumor burden during successful immune responses. Based on these observations we propose to: 1. Identify DC subsets and maturation stimuli which optimally stimulate NK cells in secondary lymphoid organs. We will address proliferation and cytokine secretion of NK cells in secondary lymphoid organs after stimulation with in vitro generated DC subtypes and DCs of secondary lymphoid organs after maturation with DC subtype specific maturation stimuli. 2. Characterize DC derived signals for NK maturation in secondary lymphoid organs. We will test DC derived IL-15 and IL-12 for KIR upregulation, induction of cytokine secretion as well as cytotoxicity and migratory behavior by NK cells of secondary lymphoid organs. 3. Determine the role of DC mediated NK activation for polarization of T cell responses in secondary lymphoid organs. We will investigate the effect of NK activation in secondary lymphoid organs on DC maturation and alloreactive as well as EBV specific T cell polarization.
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