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UBC Theses and Dissertations

Age-dependent differences in the transcriptional profile of antigen presenting cells in response to immune stimulation and infection converges on interferon response factors Wee, Kathleen


Newborns and older adults aged 65 and over have a heightened risk for severe infections, suggesting suboptimal immune responses. These two populations thus represent age-defined windows of vulnerability to infection. Antigen presenting cells (APC) are important in bridging the innate and adaptive immune systems as they express pathogen recognition receptors such as Toll-like receptors (TLR) that detect the presence of pathogens. They have been proposed to be partially responsible for the altered immunity observed at the extreme ends of the age-spectrum. However, the molecular mechanism/s that underlie this APC deficit have not been fully delineated. We chose to apply newly available cutting-edge tools to begin identifying such mechanisms. With the availability of systems biological tools to interrogate APC function, our overarching hypothesis is that age-dependent differences in the transcriptional response of APC results in functional differences in response to immune stimulation and infection. To address this hypothesis, we employed global transcriptional profiling to comprehensively investigate age-dependent differences in mRNA expression in the most important APC subsets from newborns, healthy young adults, and older adults following TLR stimulation or infection. Following TLR7/8 stimulation, neonatal DC displayed altered expression of signaling pathways involved in the response to viral pathogens. Specifically, IRF-dependent MAPK pathway genes were expressed in an age-dependent manner at baseline, while age-dependent differences in the expression of other IRF-dependent responses only occurred following stimulation. We also investigated the transcriptomic responses of monocytes to Listeria monocytogenes (Lm). Monocytes are one of the primary targets of Lm. Monocytes from newborns, young adults, and older adults differentially expressed guanylate binding proteins (GBP) in an age-dependent manner upon infection, along with significantly reduced IFN-β production in susceptible age groups, while signaling downstream of the IFN receptor complex was comparable. This suggests that age-related differences in IFN-β production in response to Lm infection led to reduced induction of GBPs in newborns and older adults compared to young adults. IFN-β production is also known to be IRF dependent. This convergence of age-dependent differences in immunity on IRF-regulated pathways begins to outline a possible molecular epicenter associated with suboptimal immune responses early and late in life.

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