Exploiting metabolic vulnerabilities of CD4 T cell subsets to control inflammatory disease

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Inflammatory diseases are often caused by inappropriate responses of effector CD4 T cells (Teff). Th17 Teff are IL17-producing CD4 T cells that contribute to a variety of immune pathologies, including Inflammatory Bowel Disease (IBD). Regulatory T cells (Treg), in contrast, suppress Teff to protect from disease. A key therapeutic objective in efforts to shift the immunologic balance towards tolerance, therefore, is to selectively inhibit Teff and promote Treg. We have shown that Th17 and Treg cells utilize fundamentally different metabolic programs, with Th17 being reliant on glucose uptake and glycolysis while Treg are primarily reliant on mitochondrial pathways. In our efforts to better understand the metabolic demands of each subset that could be targeted to selectively modulate CD4 T cells in inflammatory diseases, we have found that cytokine and inflammatory signals that drive Th17 and Treg differentiation each play distinct roles in control of T cell metabolism. Further, these metabolic changes may influence T cell fate through modulation of reactive oxygen species (ROS) and epigenetic modifications of gene expression. We showed that while Th17 require the glucose transporter Glut1 and glycolysis, FoxP3 and the Treg-inducing cytokine TGFβ inhibit this pathway and Treg can suppress independent of Glut1. Treg are metabolically flexible, however, and Toll-like receptors (TLR) ligands can stimulate Treg to increase glycolysis but with reduced suppressive capacity and expression of FoxP3. To identify additional metabolic pathways that may provide new immune modulatory targets, we performed high-resolution non-targeted metabolomics and metabolic network analyses. These studies identified glutaminolysis and one carbon metabolism as selectively enriched in Th17 relative to Treg. Here we will test the roles of Glutaminase (GLS) in glutaminolysis and Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) in and one carbon metabolism in Th17 and Treg. Treg did not require GLS, but Treg differentiation and stability were suppressed by MTHFD2. In contrast, we show that Th17 cells require both GLS, and MTHFD2. While glycolysis, glutaminolysis, and one carbon metabolism are linked and each modulate both ROS and epigenetic marks, mechanisms by which they affect Treg and Th17 cells, remain unknown. Our data have led to the hypothesis that regulation of these metabolic pathways is essential for Treg and Th17 cells through control of ROS and epigenetic methylation and that GLS or MTHFD2 will provide new immuno- modulatory targets for inflammatory diseases. We will: (1) Determine how Treg glycolysis and MTHFD2 are regulated by inflammatory cues to control Treg function and FoxP3 expression; (2) Test signals that regulate Th17 metabolism and ROS and epigenetic modifications as mechanisms by which Th17 cells require GLS and MTHFD2; (3) Establish the in vivo potential of GLS and MTHFD2 as therapeutic targets to enhance Treg and suppress Th17 cells in inflammation. These studies will establish the opportunity and mechanisms of glycolysis, GLS, and MTHFD2 to suppress Th17 and promote Treg function and stability.