NK cells are a heterogenous population of innate lymphocytes with diverse functional attributes critical for early protection from viral infections. We have previously reported a decrease in influenza-induced NK cell cytotoxicity in 6-mo-old C57BL/6 calorically restricted (CR) mice. In the current study, we extend our findings on the influence of CR on NK cell phenotype and function in the absence of infection. We demonstrate that reduced mature NK cell subsets result in increased frequencies of CD127(+) NK cells in CR mice, skewing the function of the total NK cell pool. NK cells from CR mice produced TNF-α and GM-CSF at a higher level, whereas IFN-γ production was impaired following IL-2 plus IL-12 or anti-NK1.1 stimulation. NK cells from CR mice were highly responsive to stimulation with YAC-1 cells such that CD27(-)CD11b(+) NK cells from CR mice produced granzyme B and degranulated at a higher frequency than CD27(-)CD11b(+) NK cells from ad libitum fed mice. CR has been shown to be a potent dietary intervention, yet the mechanisms by which the CR increases life span have yet to be fully understood. To our knowledge, these findings are the first in-depth analysis of the effects of caloric intake on NK cell phenotype and function and provide important implications regarding potential ways in which CR alters NK cell function prior to infection or cancer.
"For NK cells, this concept might be expandable to additional immunosuppressive mechanisms. A recent study suggested that calorically restricted mice, which have increased levels of corticosteroids, display increased frequencies of CD127 + NK cells as a consequence of a reduction of mature NK cells (Clinthorne et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Activation and expansion of T and B lymphocytes and myeloid cells are controlled by Foxp3(+) regulatory T cells (T reg cells), and their deficiency results in a fatal lympho- and myeloproliferative syndrome. A role for T reg cells in the homeostasis of innate lymphocyte lineages remained unknown. Here, we report that T reg cells restrained the expansion of immature CD127(+) NK cells, which had the unique ability to up-regulate the IL2Rα (CD25) in response to the proinflammatory cytokine IL-12. In addition, we observed the preferential accumulation of CD127(+) NK cells in mice bearing progressing tumors or suffering from chronic viral infection. CD127(+) NK cells expanded in an IL-2-dependent manner upon T reg cell depletion and were able to give rise to mature NK cells, indicating that the latter can develop through a CD25(+) intermediate stage. Thus, T reg cells restrain the IL-2-dependent CD4(+) T cell help for CD127(+) immature NK cells. These findings highlight the adaptive control of innate lymphocyte homeostasis.
Journal of Experimental Medicine 05/2013; 210(6). DOI:10.1084/jem.20122571 · 12.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings.
[Show abstract][Hide abstract] ABSTRACT: Within days after infection, natural killer (NK) cellsNatural killer (NK) cells are recruited to the lungs and play an essential role in the immune response against influenza infection. Through interactions with the virus itself, as well as viral-infected cells, NK cells secrete a variety of cytokines and can contain viral replication by killing infected cells early after influenza infection. However, the virus has means of evading NK cell responses, including escaping NK cell recognition through mutation of the viral hemagglutinin (HA) protein, regulating HA levels, and by directly infecting and destroying NK cells. Although much of our understanding of NK cell role in influenza infection has come from animal models, there is increasing information from human infection. Studies conducted during the 2009 H1N1 pandemic provided much needed information on the importance of NK cells during human infection and suggest that NK lymphopenia may correlate with increased disease severity. However, more information on how different influenza virus subtypes influence NK cell levels and activities, the role of the different NK cell receptors in infection, and the impact of NK cells on human infection, particularly in high risk populations is needed.
Current topics in microbiology and immunology 07/2014; 386. DOI:10.1007/82_2014_403 · 4.10 Impact Factor
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