Inflammatory diseases are often characterized by imbalanced ratios or functions of T effector (Teff), such as elevated Th2 and Th17 that promote asthma, and regulatory (Treg) cells, that suppress inflammation. While many such diseases can be controlled with corticosteroids, some, including severe asthma and multiple sclerosis, can show steroid (glucocorticoid; GC)-resistance and lead to increasingly negative outcomes, including death. Understanding factors that promote steroid- resistance, therefore, is critical to establish new approaches to treat GC-resistant inflammatory diseases. It is now clear that while Th2 cells are GC sensitive, steroid-resistant asthma is often characterized by the presence of IL17 producing cells, including Th17 CD4 T cells that can have intrinsic GC resistance. GC are well known to inhibit metabolism and we propose that the unique metabolism of Th17 cells contributes to their selective GC resistance. We have shown that T cell metabolism is dynamic and the Phosphatidylinositide 3-Kinase (PI3K)/Akt/mTOR Complex 1 (mTORC1) pathway induces Th17 CD4 T cells to increase glycolysis and metabolism of glutamine to glutamate for mitochondrial oxidation (glutaminolysis). Consistent with this metabolic program, we show allergen challenge increases both lactate and glutamate in bronchalveolar lavage (BAL) fluid of asthmatics and that T cells from BAL of asthma patients express the glucose transporter Glut1 at high levels. Importantly, GC resistant Th17 cells have both higher levels of glucose metabolism and glutaminolysis than GC sensitive Th2 cells. Th17 cells also have higher mitochondrial respiratory capacity and ability to withstand mitochondrial inhibition than Th2 cells. In contrast, Treg use lipid oxidation and have high levels of active AMPK, which inhibits mTORC1. Further, we show Treg are functionally impaired by high rates of glycolysis. We also show that Th17 cells rely on Glutaminase (GLS) to support glutaminolysis and differentiation, and inhibition of GLS selectively impairs Th17 cells. Elevated levels of glucose and glutamine metabolism may directly protect Th17 cells from GC, as T cells with increased Glut1 were resistant to GC-induced reactive oxygen species and cell death. Here we will test the hypothesis that allergen-induced cytokines signal T cells to induce a flexible metabolism of glycolysis and glutaminolysis that promotes GC resistance in Th17 cells and impairs Treg. To test this hypothesis we will: (1) Determine T cell metabolic programs and regulatory signals in airway inflammation and (2) Test the contribution of T cell metabolism to GC resistance of Th17 cells. Together, these studies will address a poorly understood but potentially key contributor to the pathogenesis of GC-resistant inflammatory diseases, such as severe asthma, by establishing and targeting the unique metabolic program and requirements of Th17 cells.
Inflammatory diseases are often treated with glucocorticoids, but steroid-resistant forms can emerge that can be debilitating or lead to death, such as in severe asthma. We have found that metabolic pathways are highly dynamic and exert strong effects on T cell differentiation and function. This study will examine the affect of T cell metabolism on glucocorticoid-resistance and the pathogenesis of severe asthma to determine if metabolic regulatory pathways may provide new therapeutic targets to overcome steroid resistance.
|Johnson, Marc O; Wolf, Melissa M; Madden, Matthew Z et al. (2018) Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell 175:1780-1795.e19|
|Schulte, Michael L; Fu, Allie; Zhao, Ping et al. (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24:194-202|
|Priyadharshini, Bhavana; Loschi, Michael; Newton, Ryan H et al. (2018) Cutting Edge: TGF-? and Phosphatidylinositol 3-Kinase Signals Modulate Distinct Metabolism of Regulatory T Cell Subsets. J Immunol 201:2215-2219|
|Andrejeva, Gabriela; Rathmell, Jeffrey C (2017) Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab 26:49-70|
|Liberti, Maria V; Dai, Ziwei; Wardell, Suzanne E et al. (2017) A Predictive Model for Selective Targeting of the Warburg Effect through GAPDH Inhibition with a Natural Product. Cell Metab 26:648-659.e8|