NK Cell Maturation and Function in C57BL/6 Mice Are Altered by Caloric Restriction
ABSTRACT 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.
SourceAvailable from: Jianmei W Leavenworth[Show abstract] [Hide abstract]
ABSTRACT: Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i-deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i-deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer.Proceedings of the National Academy of Sciences 12/2014; 112(2). DOI:10.1073/pnas.1423011112 · 9.81 Impact Factor
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ABSTRACT: Acute starvation, which is frequently observed in clinical practice, sometimes augments the cytolytic activity of natural killer cells against neoplastic cells. In this study, we investigated the molecular mechanisms underlying the enhancement of natural killer cell function by fasting in mice. The total number of liver resident natural killer cells in a unit weight of liver tissue obtained from C57BL/6J mice did not change after a 3-day fast, while the proportions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)+ and CD69+ natural killer cells were significantly elevated (n = 7, p <0.01), as determined by flow cytometric analysis. Furthermore, we found that TRAIL- natural killer cells that were adoptively transferred into Rag-2-/- γ chain-/- mice could convert into TRAIL+ natural killer cells in fasted mice at a higher proportion than in fed mice. Liver natural killer cells also showed high TRAIL-mediated antitumor function in response to 3-day fasting. Since these fasted mice highly expressed heat shock protein 70 (n = 7, p <0.05) in liver tissues, as determined by western blot, the role of this protein in natural killer cell activation was investigated. Treatment of liver lymphocytes with 50 µg/mL of recombinant heat shock protein 70 led to the upregulation of both TRAIL and CD69 in liver natural killer cells (n = 6, p <0.05). In addition, HSP70 neutralization by intraperitoneally injecting an anti- heat shock protein 70 monoclonal antibody into mice prior to fasting led to the downregulation of TRAIL expression (n = 6, p <0.05). These findings indicate that acute fasting enhances TRAIL-mediated liver natural killer cell activity against neoplastic cells through upregulation of heat shock protein 70.PLoS ONE 10/2014; 9(10):e110748. DOI:10.1371/journal.pone.0110748 · 3.53 Impact Factor
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ABSTRACT: BACKGROUND Prostate cancer (PCa) is a major aging-related disease for which little progress has been made in developing preventive strategies. Over the past several years, methionine restriction (MR), the feeding of a diet low in methionine (Met), has been identified as an intervention which significantly extends lifespan and reduces the onset of chronic diseases, including cancer, in laboratory animals. We, therefore, hypothesized that MR may be an effective strategy for inhibiting PCa.METHODS Control (0.86% Met) or MR (0.12% Met) diets were fed to 5-week old TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, a well-characterized model for PCa. The mice were sacrificed at 16 weeks of age and prostate and other tissues were harvested for histological and biochemical analyses.RESULTSAs previously reported, MR was associated with a decrease in body weight which was not associated with lowered food intake. MR led to significant reductions in the development of Prostatic Intraepithelial Neoplasia (PIN) lesions, specifically in the anterior and dorsal lobes of the prostate where the incidence of high-grade PIN was reduced by ∼50% (P < 0.02). The reduction in PIN severity was associated with 46–64% reductions in cell proliferation rates (P < 0.02) and plasma IGF-1 levels (P < 0.0001), which might, in part, explain the effects on carcinogenesis. Additionally, no adverse consequences of MR on immune function were observed in the TRAMP mice.CONCLUSIONS Overall, these findings indicate that MR is associated with a reduction in prostate cancer development in the TRAMP model and supports the continued development of MR as a potential PCa prevention strategy. Prostate © 2014 Wiley Periodicals, Inc.The Prostate 12/2014; 74(16). DOI:10.1002/pros.22884 · 3.57 Impact Factor