Date of Completion
Honors College Thesis
Microbiology and Molecular Genetics
Dr. Ralph Budd
necroptosis, dendritic cells, gamma delta T cells, glycolysis, immunometabolism
Gamma delta (gd) T lymphocytes are a poorly understood class of immune cells that accumulate at sites of inflammation due to infection or autoimmunity. Part of the mystery of this T cell subset derives from lack of knowledge of ligands that bind to the T cell receptor (TCR) of gd T cells. The conditions under which these ligands are induced remain ill-defined, but the Budd laboratory has recently reported that dendritic cell (DC) necroptosis exposes a previously unreported ligand for the gd TCR, leading to activation of gd T cells. Necroptosis is caspase-independent and can be induced via inhibition of caspase-8, leading to formation of a complex containing Receptor Interacting Protein Kinase 1 (RIPK1) known as the ripoptosome. In this study, we describe a new connection between glycolysis of DC and their susceptibility to necroptosis. DC grown with GM-CSF are highly glycolytic and susceptible to necroptosis induced by the pan-caspase blocker zVAD. However we demonstrate that GM-CSF-generated DCs treated with the glycolysis inhibitor 2-deoxyglucose are protected against necroptosis by zVAD. We propose that aerobic glycolysis is a prerequisite for DC necroptosis and accordingly their ability to activate gd T cells. Inhibition of glycolysis does not impact caspase activity levels, production of essential cytokines, or production of proteins essential for the ripoptosome. Instead, non-glycolytic DC have increased levels of cleaved RIPK, which serves as an inhibitor of Ripoptosome formation. It has been established that activation of DC leads to increased cellular rates of aerobic glycolysis. It may be that naïve dendritic cells are protected from necroptosis by increased cleavage of RIPK in order to prevent unnecessary cell death and the triggered activation of a downstream immune response.
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Bashant, Kathleen R., "Necroptosis of Glycolytic Dendritic Cells Enhances Activation of Gamma Delta T Cells" (2016). UVM Honors College Senior Theses. 96.