Cytotoxicity, exhaustion, and immunosenescence in CD8+ T cells during aging and infection

Abstract

Aging is associated with a decline in immune function, increasing susceptibility to infections, and reducing the efficacy of immunotherapies. This dissertation investigates the mechanisms driving CD8+ T cell dysfunction during aging, focusing on T cell exhaustion and immunosenescence during infection. Using mouse models, I examined how programmed cell death protein 1 (PD1) blockade affects CD8+ T cells in aged mice exposed to lethal microbial exposure (NME). I demonstrate that infection exacerbates CD8+ T cell exhaustion in aged mice, with increased expression of inhibitory receptors (PD1) and diminished effector function. PD1 checkpoint blockade improved survival in old mice by enhancing CD8+ T cell cytotoxic capacity, without increasing inflammation. To further characterize functional capacity, I validated an in vivo assay to assess degranulation (cytotoxicity) in old mice. Using this approach, I found that CD8+ T cells from old mice retain the ability to degranulate in vivo upon aCD3 stimulation, but not during LCMV-Armstrong or Cohousing (CoH or NME). Finally, I explored how the duration and timing of antigen exposure and cytokines, such as interleukin-10 (IL-10), alter CD8+ T cell exhaustion. I determined that long-term NME exposure reduces inflammatory cytokine gene expression and the frequency of CD8+ CD44+ PD1+ T cells. Additionally, IL-10 neutralization ablates the protective effects of anti-PD1 during NME challenge. Together, these studies provide mechanistic insight into how age and environmental challenges impair CD8+ T cell function. My findings reveal potential therapeutic strategies to restore CD8+ T cell function and resilience in aged individuals.