The dynamic role of natural killer (NK) cells in immunology has been demonstrated in numerous fashions, proving they are much more than "natural killers". However, NK cells are perhaps still the least well understood lymphocyte, due to their relatively low abundance and the limited transgenic models available for study. An innate immune cell that plays a critical role in providing early immunity against viral infections and cancers, NK cells are becoming increasingly recognized for shaping and directing immune responses. Accounting for approximately 5-25% of peripheral blood mononuclear cells in humans and 5-10% of lymphocytes in murine circulation, NK cells have very similar functional attributes in both species, making mice an ideal model system for the study of NK cell biology. Studies in mice have revealed the critical importance of NK cells in providing tumor surveillance as well as early protection from viral infections. Preclinical studies have underscored the utility of using NK cells as an immunotherapeutic technique to combat various cancers, while NK cell function is often associated with positive or negative outcomes in various disease states. Furthermore, various lifestyle factors have been found to positively or negatively influence NK cell function. Among these lifestyle factors, diet has gained notoriety as being capable of influencing the homeostasis and function of NK cells. However, the mechanisms by which diet influences NK cells are not fully understood, highlighting the need for a better understanding of the molecular and cellular mechanisms by which diet influences NK cell development. Thus, our laboratory has extensively studied the effects of the restriction of energy intake, or caloric restriction (CR) on NK cell function and biology at the organismal, cellular, and molecular level. Here we describe a series of experiments investigating the role of energy intake on immunity to influenza virus, with a focus on NK cells. We describe a series of studies that identify the specific changes to NK cells induced by CR, both beneficial and potentially damaging. In these experiments we show that CR results in fewer NK cells with a mature phenotype, and that expression of transcription factors critical for NK cell maturation are reduced by CR. We also demonstrate that thymic derived NK cells are present in normal numbers in CR mice and have enhanced function. In a series of experiments demonstrating the intricate relationship between immunity and metabolism we show how refeeding of CR mice restores NK cell homeostasis and function, both before, and during influenza infection. Using in vitro techniques combined with ex vivo analysis of metabolic signaling pathways, we provide potential mechanisms by which CR impairs NK cell maturation. These studies serve to highlight the critical role of optimal nutrition in maintaining NK cell homeostasis and function. To our knowledge, this dissertation is the first data presented that clearly details the effects of CR on NK cell development and homeostasis, as well as the molecular and biochemical pathways mediating this effect.
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