Der Einfluss von metabolischen Veränderungen auf Immunantworten.
Zusammenfassung der Projektergebnisse
Type 1 IFNs and IL-18 increase NK cell function by upregulating cMyc-dependent iron metabolism. NK cells are important early responders against viral infections and cancer. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction. However, very little is known about the metabolic requirements of NK cells in general and importance for activation and function of these cells. Type 1 interferons are important for early and fast activation of NK cells. However, how IFN signaling exert its effect is only partially understood. We found, that IFNs in combination with IL-18, but not IL-12/IL-2, very effectively induced production of IFNγ and Granzyme B in NK cells as early as 4h post-stimulation. This 12 enhanced functionality was sustained after longer stimulations of 18h. NK cell cytotoxicity was also elevated after the stimulation with IL-18 and IFNs in comparison to IL-18 or IFNs alone. In the first hours after stimulation with IFNs+IL-18 cMyc was increased, following by an enhanced upregulation of transferrin receptor (CD71) and transferrin-iron uptake at later time points. Inhibition of iron uptake abolished IFN-dependent increase of IFNγ and granzyme B of NK cells. The adoptive transfer of IL-18 + IFNβ stimulated NK cells more effectively reduced the growth of established B16 melanomas, which was accompanied by an increased tumor infiltration of activated NK cells. In summary, our data suggest that type 1 interferons cooperate with IL-18, but not IL-2/IL-12, to enhance NK cell function through promoting cMyc signaling and iron-dependent metabolism.
