A Clonal, Transcriptomic, and Functional Analysis of T-cells Mobilized to Blood in Response to Acute Exercise

Abstract

Regular participation in physical activity induces remarkable health benefits that are associated with immediate (e.g. improved sleep quality, reduction in subjective stress) and long-term effects (e.g. decreased risk and incidence of cardiovascular disease/cancer). Emerging evidence has also determined that physical activity lowers the risk of infection and mortality caused by virus’ such as SARS-CoV-2. Indeed, there is a compelling link between physical activity and the body’s defense system that has prompted the investigation of immune modulation via exercise. Over the last few decades, it has been established that both chronic and acute exercise act as an immune system adjuvant that improves defense mechanisms to reduce the incidence of disease and boost anti-viral activity. One mechanism by which exercise enhances systemic immune function is through the redistribution of leukocytes with each exercise bout; a response that is driven by catecholamines and purported to increase host immune surveillance. The robust exercise-induced mobilization of responsive immune cells (e.g. natural killer cells, CD8+ T-cells) display favorable phenotypes associated with enhanced lytic function against tumor and virus cells, increased trafficking ability, greater response to cytokines, and augmented response to cognate antigens. Technological advances in system biology analysis (e.g. transcriptomics) would provide a greater comprehensive phenotype of exercise responsive cells, including preferentially mobilized T-cell subsets. Therefore, assessment of the T-cell receptor (TCR) repertoire, is vital to deepen our understanding of the beneficial effect of acute exercise on immune cell phenotype and function. Furthermore, utilizing multimodal sequencing analysis would elucidate the transcriptomic changes induced by acute exercise at an individual cell level. In addition, our lab has proposed that exercise-mobilized cells may provide excellent precursors for the isolation and manufacture of several cell therapeutics used to treat hematological cancers. Therefore, it is necessary to determine the capacity by which exercise has application across different cell products utilized for immunotherapy. Consequently, the summation of effects induced by acute exercise over time, may improve immunosurveillance against viral pathogens, providing beneficial anti-viral effects. While exercise has been shown to promote anti-viral immunity, the mechanisms by which exercise can ameliorate symptoms and enhance synthetic immunity against SARS-CoV-2 is still under investigation. Herein, this dissertation explores the effects of acute exercise in humans on T-cell diversity and function, the manufacturing of adoptive cell therapeutic CIK cells, and the COVID-19 vaccine induced immune response. Cumulatively, these data enhance our understanding of the exercise-induced immune changes that occur within T-cells at the clonal and transcriptional level, and provides insight for the translational potential of acute exercise to improve immune responses to viruses and cancer in a clinical setting.