DEFINING THE ROLES OF DEVELOPMENT, METABOLISM, AND THE ENVIRONMENT IN THE CD8+ T CELL RESPONSE TO INFECTION

177 pagesIn contrast to adults, neonates experience high morbidity and mortality from recurrent intracellular infections. CD8+ T cells are responsible for killing intracellularly infected cells. Therefore, uncovering the mechanisms that regulate age-related differences in the CD8+ T cell compartment will allow us to develop approaches to enhance immunity for this vulnerable population. Neonatal CD8+ T cells provide robust protection early in infection but become terminally differentiated and lose their ability to form memory whereas adult CD8+ T cells excel at memory formation. The mechanisms that instruct neonatal and adult CD8+ T cells to adopt divergent fates following infection are unknown. In this dissertation, I investigated the cellular and molecular mechanisms that promote the neonatal program of immunity. The conventional theory is that the neonatal immune system is immature because their CD8+ T cells are younger and have undergone less post-thymic maturation. However, I show neonatal CD8+ T cells are not immature, rather, CD8+ T cells made at different times of life arise distinct progenitors give rise to unique protective programs. Next, I asked whether differences in metabolic programming contribute to the age-related program of protection. I discovered Lin28b promotes elevated levels of glycolysis in neonates and blockading neonatal cell entry into glycolysis led to sufficient memory formation and recall responses. Finally, fetal- and adult-derived CD8+ T cells co-exist in adulthood but we do not know if the developmental architecture can be modified or if the functions of fetal-derived cells can be altered. In the fourth chapter, I developed a novel approach to expose mice to a diverse microbial environment for the entirety of early development. I found high microbial exposure in early life allowed fetal-derived cells to integrate into the adult CD8+ T cell compartment at higher proportions and enhance their protective capabilities. Ultimately, my doctoral work shows neonatal CD8+ T cells represent a distinct population that is uniquely suited to respond to the challenges present in early life. Findings from my dissertation will contribute to the conceptual framework that explains CD8+ T cell ontogeny, how individual variation in cell-mediated immune responses arises, and the programs that underlie immune cell instruction.2024-06-0