| During human aging, the immune system undergoes a significant number of global changes, a process termed `immunosenescence'. These alterations are associated with increased susceptibility to infections, reduced vaccine effectiveness, higher incidence of metabolic, autoimmune and neoplastic pathologies, and a chronic state of low-grade inflammation. A hallmark feature of immunosenescence is the progressive accumulation of late-differentiated CD8+ T cells with features of replicative senescence, including irreversible cell cycle arrest, loss of CD28 surface expression, shortened telomeres, downregulation of telomerase activity, and an altered cytokine profile. CD8+ T cell senescence is thought to contribute to dysregulated immunity, chronic diseases that are exacerbated by excess inflammation, and increased morbidity and mortality. Chronic HIV disease, even when controlled by antiretroviral therapy (ART), is associated with accelerated progression of CD8+ T cells to replicative senescence. This dissertation focuses on a variety of previously unexplored facets of CD8+ T cell replicative senescence of CD8+ T cells, namely the identification of novel biomarkers of senescence, as well the effects of important inflammatory immunomodulators on the senescence trajectory in vitro. An overview of the background on aging, replicative senescence and its immune effects is provided in Chapter 1.;Chapter 2 describes our studies aimed at evaluating the expression of several novel biomarkers of senescence on CD8+ T cells in the context of HIV disease. Refining the senescence signature has the potential to provide a more clinically relevant assessment of adaptive immune status in HIV-infected persons. We examined the relationship between adenosine deaminase (ADA), glucose transporter 1 (GLUT1), and leucine rich repeat neuronal 3 (LRRN3) expression and CD38 positivity, which is a robust predictive marker for HIV/AIDS disease progression. The main finding of our analysis is that low ecto-ADA expression was strongly associated with high CD38 expression on CD8+ T cells. In chapter 3, we describe our studies on the effects of a common lipid immunomodulator, prostaglandin E2, which is secreted in large quantities by cancer cells and aged antigen presenting cells, on the CD8+ T cell senescence trajectory. We found that PGE2 and its free radical catalyzed isoform strongly suppressed key T cell functions and induced faster progression to replicative senescence. In the final chapter, our studies evaluating the impact of C-reactive protein, a powerful prognostic indicator of many acute and chronic inflammatory pathologies, on T cell function and pro-inflammatory pathways are described. We observed upregulation of the NF-kappaB pathway, as well as higher levels of secreted TNF-alpha; and reactive oxygen species when T cells were treated with CRP prior to activation. Collectively, the studies described herein help refine the immunological signature of replicative senescence as well as the effects of inflammation on this important facet of CD8+ T cell biology. |
