This application proposes a 5 year program to provide the candidate with mentored scientific training and career development guidance. The long term goal of the candidate is to be an independent physician-scientist at an academic medical center, investigating the innate immune response and potential mechanisms of enhancing this immune system for the treatment of pediatric disease. The proposed work will be performed at Washington University in St. Louis under the mentorship of Dr. Wayne Yokoyama, an accomplished immunologist and physician-scientist. The immune response to infection is mediated by two broad arms, the innate and adaptive immune systems. One classical distinction between innate and adaptive immunity is the restriction of immunologic memory to adaptive T and B lymphocytes. Innate immune cells are a first-line defense against pathogens and are thought to respond consistently to infection, regardless of previous exposure, i.e., they do not exhibit memory of prior activation. Natural killer (NK) cells are innate lymphocytes capable of recognizing and killing target cells and producing immunoregulatory cytokines, especially IFN-?. NK cells are important for the initial control of a variety of pathogens, and defects in NK cells lead to uncontrolled, fatal infections. Preliminary studies utilizing an adoptive transfer system demonstrate that NK cells with a history of prior cytokine activation exhibit an NK-intrinsic, enhanced capacity to produce IFN-? upon re- stimulation. This memory-like property appears to be both stable and heritable. The proposed experiments will further characterize memory-like NK cells in vitro and in vivo and investigate the mechanisms of NK cell memory. The specific aims are to: (1) Determine the functional attributes of memory-like NK cells and if cytotoxic memory-like NK cells can be generated; (2) Determine if memory-like NK cells differentiate in vivo in response to pathogens; and (3) Determine if enhanced IFN-? production by memory-like NK cells is controlled transcriptionally, by epigenetic modifications, and/or post-transcriptionally. These studies have clinical relevance, since patients whose adaptive immune systems are immature or dysfunctional, such as neonates or immunocompromised patients, may benefit from augmentation of their intact innate immune NK cell response. Natural killer cells are a key component of the innate immune response and provide protection against a variety of infections. These experiments explore fundamental mechanisms by which natural killer cells and the innate immune system may be enhanced based on prior experiences. This area of research may lead to improved therapies to augment the immune response and treat infections.