Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Nursing

First Advisor

Connie Ulrich

Abstract

Life is full of stressors that challenge our health; recent evidence suggests that chronic stress leads to altered immune outcomes in humans. While the literature illustrates the chronic stress-induced changes in immune outcomes, there is limited understanding of the impact of a chronic stress response on specific immune cell subsets. The primary objective of this dissertation is to examine the effect of a stress hormone and the stress of caregiving on immune cell subsets, specifically CD8 T cells. To address this objective, we perform an in vitro experiment with isolated CD8 T cell subsets (naïve, central memory, effector memory) from human adults and treated them with stress-related hormone, norepinephrine (NE). We also perform a cross-sectional matched study of CD8 T cell subsets from twenty-one family caregivers of stem cell transplant recipients and twenty age- and gender-matched controls at the National Institutes of Health Clinical Center. In CD8 T cell subsets, we conducted flow cytometry analysis for immunophenotyping, RT-qPCR and a microarray for gene expression changes, and ELISA for protein level assessments on the impact of NE. We examined differences using t-tests and gene set enrichment analysis (GSEA) for global gene expression analysis of mRNA changes in NE treated and untreated CD8 central memory T cells. We were the first to report that memory CD8 T cells express higher levels of the NE receptor, beta-2 adrenergic receptor, compared to naïve cells. We found memory CD8 T cells had an increase in the mRNA levels of pro-inflammatory cytokines and chemokines before and after activation and a decrease in proliferation-related cytokines after activation. Protein levels were also significantly increased in pro-inflammatory cytokines and decreased in proliferation-related cytokines. Individuals with high levels of NE in their serum, or were family caregivers, had a pro-inflammatory state before and after antigenic challenge of memory CD8 T cells. These findings suggest chronically stressed individuals may be more susceptible to previously encountered antigenic challenges compared to novel challenges. Future research should explore the exact mechanisms behind these stress-related changes in memory CD8 T cells and the longitudinal consequences on immunity in chronically stressed populations.

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