Differential Maintenance, Function, and Transcriptional Profile of CD8⁺ T cells with Age
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PublisherThe University of Arizona.
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AbstractInfectious diseases remain amongst leading causes of death in people aged 65 years and older; therefore, much research is focused on determining the immune components that contribute to age-dependent increased susceptibility to, and increased mortality from, infections. CD8⁺ T cells are critical for clearing intracellular pathogens through production of cytokines and direct killing of infected cells. Age-dependent CD8⁺ T cell alterations have been described, including decreased numbers of naïve CD8⁺ T cell precursors and decreased numbers and function during infection. This dissertation explores the mechanisms contributing to these changes. First, we demonstrated that multiple mechanisms contribute to changes in the CD8⁺ T cell pool with age. CD8⁺ T cells from unimmunized T cell receptor transgenic (TCRTg) old mice undergo massive virtual memory (VM) conversion with age; both homeostatic proliferation and cross-reactivity may contribute to the generation and accumulation of VM cells with age. These VM cells exhibit an age-dependent replicative impairment to cognate antigen, which points to possible detrimental functional consequences due to changes in the overall T cell pool. Second, we evaluated the cell intrinsic contribution to the decreased old CD8⁺ T cell response. With in vitro stimulation, old CD8⁺ T cells exhibit decreased ability to enter into late cell divisions and decreased production of effector molecules. In addition, we found that old CD8⁺ T cells have decreased expression of the master transcription factor T-bet, which correlates to decreased effector function and terminal differentiation in vivo. Collectively, these results identify possible cell-intrinsic targets for improving CD8⁺ T cell immunity. Finally, we measured whether a Listera monocytogenes live vaccine model induces protective immune responses in old mice. We found that vaccination conferred little protection in old mice upon pathogen challenge. These results contrast with other vaccine models, which may allow for pinpointing both the vaccine and immune components required for generating strong protective immunity in the elderly. Collectively, this dissertation demonstrates that CD8⁺ T cell precursors, effector cells, and memory cells exhibit profound changes with, age and identifies both possible mechanisms contributing to these alterations as well as possible therapeutic/vaccine targets for improving immunity in the elderly.
Degree ProgramGraduate College