Exercise-dependent modulation of natural killer cells during human growth

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Natural killer (NK) cells are a dynamic subset of lymphocytes that drive the innate and adaptive immune response. NK cells are the most responsive immune cell to acute exercise, a form of physiological stress. Children and older adults demonstrate a dampened NK cell response to specific episodes of exercise compared with young adults. Unfortunately, these data are based on cross-sectional studies and seldom concurrently examine NK cell function. Studying acute changes in NK cells is important because downregulation of NK cell number and/or function can have summative negative effects on the immune system. By studying the effects of physiological stress in the form of exercise, further discovery of the NK cell response in the context of human growth may provide unique insights into the mechanisms that regulate NK cell mobilization, maturation, and function.OBJECTIVESThe long-term goal of my research program is to understand the effects of specific episodes of exercise on natural killer cells during human growth. My short-term objectives are to:1. Characterize the effect of different types of exercise on NK cell subsets and function;2. Quantify the effects of growth and maturation on exercise-induced changes in NK cell phenotype, which comprises NK subsets as well as NK receptor expression, density, and diversity; 3. Clarify the contributions of NK cell properties and the systemic environment to the NK cell response to acute exercise.METHODSObjective #1: Much of the literature in children has examined the effects of continuous exercise on NK cell subsets, but there is little evidence to inform NK cell function and how different types of exercise may regulate NK cells. Boys and girls will complete 4 distinct types of exercise in a randomized fashion. Pre- and post-exercise blood samples will be used to quantify NK cell subsets (CD56bright, and CD56dim), and function (cytotoxic activity per NK cell) by flow cytometry. Objective #2: I will use a longitudinal study design to examine the effects of growth and maturation on NK phenotype to further our understanding of sensitive growth phases whereby exercise may influence NK cell function. Pre and post pubertal boys and girls will be assessed annually over 4 years. Exercise-induced changes NK cells and NK receptor expression, density, and diversity with exercise and over time. Objective #3: The processes of NK cell maturation and mobilization are driven by an interaction between circulating NK cell properties and the systemic microenvironment. I will use in vitro experiments with samples collected in Objective #2 to examine the extent to which these contribute to the response to exercise. NK cells will be isolated from resting blood samples and incubated with post-exercise cell-free serum. A portion of each sample will be assessed by flow cytometry for NK cell phenotype, with the remaining co-cultured with target cells to induce NK cell cytotoxic activity.