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

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dc.contributor.authorTabilas, Cybelle
dc.contributor.chairRudd, Brian D.
dc.contributor.committeeMemberBrito, Ilana Lauren
dc.contributor.committeeMemberWojno, Elia Tait
dc.contributor.committeeMemberBynoe, Margaret S.
dc.date.accessioned2022-09-15T15:51:30Z
dc.date.issued2022-05
dc.description177 pages
dc.description.abstractIn 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.
dc.identifier.doihttps://doi.org/10.7298/1c1z-hc42
dc.identifier.otherTabilas_cornellgrad_0058F_12284
dc.identifier.otherhttp://dissertations.umi.com/cornellgrad:12284
dc.identifier.urihttps://hdl.handle.net/1813/111800
dc.language.isoen
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCD8+ T CELLS
dc.subjectdevelopmental layering
dc.subjectmetabolism
dc.subjectpet shop mice
dc.subjectRTEs
dc.subjectvirtual memory cells
dc.titleDEFINING THE ROLES OF DEVELOPMENT, METABOLISM, AND THE ENVIRONMENT IN THE CD8+ T CELL RESPONSE TO INFECTION
dc.typedissertation or thesis
dcterms.licensehttps://hdl.handle.net/1813/59810.2
thesis.degree.disciplineBiomedical and Biological Sciences
thesis.degree.grantorCornell University
thesis.degree.levelDoctor of Philosophy
thesis.degree.namePh. D., Biomedical and Biological Sciences

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