Date of Award

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular, Molecular and Biomedical Sciences

First Advisor

Eyal Amiel

Abstract

Dendritic cells (DCs) are the most potent professional antigen presenting cells (pAPCs) of the immune system and play a fundamental role in coordinating innate and adaptive immune responses. Through the expression of a wide array of pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), DCs recognize a variety of microbial pathogens and infectious stimuli. Stimulation of DCs through TLR ligation results in a rapid series of activation-associated events, termed "maturation," which include the upregulation of surface co-stimulatory molecule expression, inflammatory cytokine secretion, and stimulation of naïve T cells via antigen presentation by MHC molecules.

Activation of DCs through TLRs is coupled with an increased metabolic demand fulfilled by a rapid change in DC glucose metabolism and characterized by increased aerobic glycolysis rates. TLR-driven glycolytic reprogramming plays an essential role in generating building blocks required for high level protein synthesis associated with maturation. Although glucose imported from extracellular environments has been broadly considered as the major driver of glycolytic metabolism in immune cells, the contributions of intracellular glucose stores to these processes are not well-defined. The role of intracellular stores of glucose, in the form of glycogen, is widely appreciated in non-immune systems. However, very little is known about the implication of glycogen metabolism in DC immune responses. This work unveils the role and potential regulatory mechanisms of glycogen metabolism in support of DC effector function.

The first part of this work primarily focuses on our characterization of the role of glycogen metabolism in early DC activation responses; while in the last chapter, we describe a potential regulatory mechanism of DC glycogen metabolism by activation-associated nitric oxide (NO) production. In this work, we tested the overarching hypothesis that DC-intrinsic glycogen metabolism supports the early glycolytic reprogramming required for effector responses and that nitric oxide can regulate this metabolism. We demonstrate that DCs possess the enzymes required for glycogen metabolic machinery and that glycogen metabolism supports DC immune effector response, particularly during early activation and in nutrient-limited environments. More importantly, we uncover a very intriguing metabolic phenomenon, in which DCs engage in the differential metabolic pathways driven by carbons derived distinctively from glycogen and free glucose. Our studies present the fundamental role and regulatory mechanisms of DC-intrinsic glycogen metabolism and underline the differential utilization of glycogen and glucose metabolism to support their effector responses. Overall, this work adds to a growing field of immuno-metabolism an improved understanding of an intricate layer of metabolic mechanisms that immune cells undertake in response to immune stimuli.

Language

en

Number of Pages

273 p.

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