Dendritic cells (DCs) are potent professional antigen presenting cells of the immune system and serve as a bridge between innate and adaptive immune responses. When DCs are activated by a stimulus through toll- like receptors (TLRs), DCs undergo a process of maturation, defined by cytokine & chemokine secretion, co- stimulatory molecule expression, antigen processing and presentation, and the ability to activate T cells. DC maturation is coupled with an increase in energy demand, which is fulfilled by a TLR-driven burst in glycolytic metabolism. Up-regulation of glycolysis in activated DCs provides these cells with molecular building blocks and cellular energy required for DC effector function. Inhibition of glycolysis impairs both the survival and effector function of activated DCs. According to the prevailing model in the field of DC ?immunometabolism?, TLR-driven glycolysis in DCs is sustained primarily by increases in glucose uptake. While non-immune cells, specifically hepatocytes and muscle cells, can store glucose in the form of glycogen as an intracellular energy reserve, the role of glycogen metabolism in supporting DC immune responses has not been described. Our preliminary data show that DCs express enzymes essential for glycogen metabolism and that inhibition of glycogen metabolism significantly impairs key activation parameters of these cells. This indicates that glycogen metabolism in DCs may play an important role in supporting the effector function of DCs. This proposal aims to answer how glycogen metabolism regulates and supports the course of immune activation in DCs. We propose using a combination of pharmacological and genetic approaches in both human and mouse DC systems to test the hypothesis that glycogen metabolism is an essential component of DC energy homeostasis that is required for supporting effective immune functions of these cells. !

Public Health Relevance

Dendritic cells (DCs) play a fundamental role in controlling pathogenic infection and stimulating lymphocytes of the immune system. Recent advances in the field have defined the importance of glucose metabolism to support the immune function of DCs. This proposal will examine glucose storage in the form of glycogen within DCs, as an important intracellular nutrient source during the activation of these cells. This work has the potential to inform both vaccine and cellular immune therapy strategies. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI135385-02
Application #
9652799
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Vazquez-Maldonado, Nancy
Project Start
2018-02-19
Project End
2021-01-31
Budget Start
2019-02-01
Budget End
2021-01-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Other Health Professions
Type
Sch Allied Health Professions
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405