Regulation of virus-specific natural killer cell memory by IL-10 and TGF-β (CCR4P.207)

Natural killer (NK) cells are critical for host control of viral infections and are rapidly activated by pro-inflammatory cytokines. These activating cytokines are thought to be counter-balanced by regulatory cytokines to prevent excessive cytotoxicity or inflammation. This study investigates the role of the immunosuppressive cytokines transforming growth factor (TGF)-β and interleukin (IL)-10 in NK cell development and function, particularly in the generation of effector and memory responses against viral infection. We compared TGF-β-insensitive NK cells (using TGF-βRII fl/fl x NKp46 iCre mice) to NK cells from littermate control mice directly, as well as in mixed bone marrow chimera and adoptive transfer settings. Although they exhibited no obvious defect at steady state, TGF-β-insensitive NK cells revealed greater activation but decreased memory cell formation during mouse cytomegalovirus (MCMV) infection. Conversely, IL-10R-deficient mice at steady state contained greater percentages of mature NK cells in all organs. Similar to TGF-β-insensitive NK cells, IL-10R-deficient NK cells were also defective in generation of memory following MCMV infection. These studies reveal a novel and important role for immunosuppressive cytokines in regulating the magnitude of the effector response and in the optimal generation of long-lived NK cells following viral infection.