Determining the contribution of glutaminase-dependent metabolism of dendritic cells to inflammatory diseases

PROJECT SUMMARY Dendritic cells (DCs) are professional antigen-presenting cells that initiate T-cell mediated inflammation or support tolerance to self- and environmental antigens. However, it remains unclear how DCs are programmed to choose between driving inflammation versus immune tolerance. During immune activation, DCs profoundly rewire their intracellular metabolic pathways to perform their functions and interact with T cells. However, the molecular mechanisms connecting metabolic changes in activated DCs to their immune functions are not completely understood. We propose that understanding the metabolic processes of DCs during antigen presentation offers an avenue for the discovery of novel mechanisms of inflammation and immune tolerance. Research from our group and others has shown that the metabolism of DCs regulates cytokine secretion and antigen presentation. We showed that DCs highly express the rate-limiting mitochondrial enzyme Glutaminase (GLS) that converts the most abundant circulating amino acid glutamine to glutamate. Our new data suggest that GLS is a metabolic checkpoint that controls DC maturation and activation and enhances antigen-presentation to CD4 and CD8 T cells. The central hypothesis of this project is that glutamine metabolism in DCs directly controls their choice during antigen presentation between activating pro-inflammatory T cells and priming regulatory T cells to establish tolerance. We will capitalize on novel mouse models of GLS deficiency in DCs and a combination of experimental and systems immunology approaches to identify molecular mechanisms of how Glutaminase-dependent metabolism in DCs controls inflammation and tolerance by following two complementary aims. In Aim 1 we will determine how GLS activity in DCs regulates antigen presentation and inflammation. To this end, we will decipher how GLS regulates intracellular metabolism, pro-inflammatory signaling pathways, gene expression and antigen processing and presentation in DCs during activation and maturation. In Aim 2 we will identify cellular and molecular mechanisms that connect GLS-expressing DCs to inflammatory diseases. We will determine how GLS and glutamine metabolism reshape the crosstalk between DCs and T cells in an antigen-driven model of atopic dermatitis and a genetic model of psoriasis. This project will identify new molecular mechanisms connecting metabolism to antigen-driven inflammation and direct novel interventions to target GLS in DCs to control pathological inflammation, allergy, and tissue damage.