T effector (Teff) cells induce and require glycolytic pathways and increase their uptake of glucose to have energy for activation and proliferation. Teff cells, specifically Th2 and Th17 subsets, are found in the airway inflammation present during asthma. As disease increases in severity, there is a shift to an IL-17 predominant and highly Th17-enriched response. Treatments of asthmatic patients include the use of glucocorticoid (GC) steroids. These drugs are effective at controlling inflammation in mild cases, but Th17 cells have been shown to have an intrinsic resistance to GCs and their increasing abundance in severe asthma contributes to a general resistance of these patients to GC treatment. A key therapeutic objective, therefore, is to identify mechanisms that contribute to Th17 resistance to GC and targets that may be exploited to increase sensitivity of Th17 cells to GCs. One potential target may be cell metabolism. GCs are well known to modulate metabolism and our preliminary studies show GC to decrease mitochondrial capacity. Further, studies have shown that cells that have increased glycolysis and oxidative phosphorylation are more resistant to the effects of GCs. The Rathmell lab including my preliminary data has now shown through biochemical approaches that Th17 cells have a unique metabolism in that they are glycolytic and have a high mitochondrial capacity which is fueled by glucose and glutamine metabolism and may contribute to the intrinsic resistance of these cells to GCs. We propose to identify metabolic pathways that are altered in airway inflammation and in GC-resistant T cells. We hypothesize that high levels of glycolysis in T cells are essential for airway inflammation in asthma and that Th17 cells promote GC resistance due to their greater mitochondrial oxidative capacity and higher use of glutaminolysis. Greater flux through these pathways would increase the ability of Th17 cells to manage metabolic and oxidative stress. However, the in vivo metabolism of Th2 and Th17 cells that may contribute to disease remains poorly understood. To better understand T cell metabolism and test our hypothesis, we will: (1) Determine if differences in the metabolic programs of Th2 and Th17 cells drive their response in a mouse model of airway inflammation and (2) Identify the effects of glucocorticoids on the metabolic programming of Teff cells in a mouse model of airway inflammation. Our goal is to test a potentially new mechanism of GC resistance in asthma in which the metabolism of Th17 cells contributes to therapy- resistance. These studies will establish the key metabolic targets that may contribute to GC-resistance in Th17 cells during airway inflammation to ultimately identify new targets to increase GC-sensitivity in those cells.
Asthma is one of many diseases that is controlled with glucocorticoids however long-term use can lead to glucocorticoid resistance. We have shown that T cells have varied metabolism needed for differentiation and function. The aim of this study is to identify how the metabolic programs of T cell subsets contribute to the development of resistance to glucocorticoids and determine metabolic targets that can overcome resistance.