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Advisory Committee Chair

Chander Raman

Advisory Committee Members

Robinna Lorenz

Troy Randall

Hui Hu

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Autoimmunity is propagated through the lack of effective mechanisms of central and peripheral tolerance. In relapsing remitting multiple sclerosis (RRMS), dysregulated adaptive immune cells have been shown to contribute to disease morbidity through the influence of immune-modulating cytokines in the peripheral blood. Interleukin-2 (IL-2) is a cytokine with several key functions in regulating homeostatic mechanisms within the human immune system. Interferon gamma (IFNγ) is a type II interferon that is needed for an effective response to intracellular bacteria infection through the actions of Th1 cells. IL-2 and IFNγ signaling occurs primarily through signal transducer and activator of transcription (STAT) activation. Genome-wide association studies (GWAS) have determined that single nucleotide polymorphisms in gene loci for IFNγ and IL-2 contribute to disease susceptibility and progression in MS. The role that IL-2/IFNγ play in the concurrent activation of CD4+ and CD8+ T lymphocytes in the context of early treatment naïve individuals with RRMS is equivocal. This study examined the outcome of IL-2 and/or IFNγ induced stimulation and found distinct signaling outcomes, over short stimulation durations, that led to phenotypic changes in subsets of regulatory and non-regulatory CD4+ and CD8+ T lymphocytes. Furthermore, we showed that over the course of short term IL-2 induced STAT5 signaling and IL-2 dependent IFNγ induced STAT1 activation, the proportion of various effector CD4+ and CD8+ T lymphocytes subsets from patients with RRMS exhibited specific hyperactivation responses. Through unbiased approaches of phenotypic comparison in these cells, we uncovered heterogeneous populations of non regulatory and regulatory lymphocytes in healthy individuals and/or patients with RRMS. Moreover, in this treatment naïve cohort of RRMS patients, we saw that STAT1 or STAT5 activation did not correlate with common measures of disease status in IFNγ dependent STAT1 activation, IL-2 dependent STAT5 activation, or in IL-2 induced IFNγ dependent STAT1 activation. These approaches can better identify STAT dependent immune cell activation and functional outcomes, independent of clinical disease measures that assay disease accumulation. These findings apply to approaches that could potentially identify more effective therapeutic measures that constrain CD4+ and CD8+ T lymphocytes in the context of early treatment naïve individuals with RRMS.

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