The goal of the Rathmell lab is to establish the regulation and role of metabolic pathways in lymphocyte activation, differentiation, and transformation. This work includes studies on both immunologic and cancer metabolism aiming to identify mechanisms by which cell metabolism modulates (1) inflammatory diseases and (2) growth and proliferation of cancer cells. To achieve this goal we have three main project areas.
1) We are examining the regulation of metabolism of T cell subsets. T lymphocytes are important to drive and control immunity and inflammation. We have shown that T cell activation in response to infection or autoimmunity leads to a dramatic metabolic reprogramming from oxidative metabolism that largely supports energy generation to a highly glycolytic metabolism that can promote biosynthesis and cell growth (1,2,3). If this metabolic reprogramming does not occur, T cells are unable to activate or grow, thus protecting from inflammatory diseases. Importantly, T cells also differentiate as activation progresses and we have found that different T cell subsets utilize distinct metabolic programs (4). The most inflammatory T cells become the most highly glycolytic, while the immune suppressive regulatory T cells (Treg) become least glycolytic and instead rely on mitochondrial oxidative pathways. The specific metabolic differences between these subsets may allow metabolic targeting or modulation in multiple inflammatory settings. We are now examining this possibility with the support of the NHLBI, the Alliance for Lupus Research, and the Crohn’s and Colitis Foundation of America.
2) We are also using genetic approaches to identify metabolic pathways that are essential for T cell activation and establishment of functional subsets. This work has focused on the glucose transporter Glut1 to date. We have found that Glut1 overexpression in T cells can augment T cell activation (1) and is sufficient to lead to an inflammatory disorder as mice age that resembles Systemic Lupus Erythematosus. Glut1 is regulated by activation of the PI3K/Akt signaling pathway (5) and ectopic activation of this pathway leads to a similar inflammatory phenotype (6). We are now using a variety of conditional gene knockout animal models and siRNA for metabolic genes in glycolysis, glutamine metabolism, and other pathways to test the role of these pathways in vivo in models of inflammatory disease.
3) The metabolic regulation of leukemic cell proliferation and survival is also a key area of investigation in the Rathmell lab. These studies focus on acute lymphoblastic leukemia (ALL) of both T cell and B cell origins. Our focus is to define how leukemic transformation alters lymphocyte metabolism to identify similarities and differences with normal immune activation of these cells and to determine how targeting these metabolic pathways impact the fate of leukemic cells. This work combines cancer metabolism with mechanisms of cell death and we have found that inhibition of glucose metabolism leads to alterations of Bcl-2 family proteins that are essential to allow cells to undergo apoptosis (7,8,9). By genetically targeting metabolic pathways in vivo we are now testing the metabolic adaptation and stress response of cancer cells to metabolic inhibition. These studies have been supported through the NCI, Leukemia and Lymphoma Society as well as Alex’s Lemonade Stand and Gabrielle’s Angel Foundation.
Our approach to study the mechanism and role of metabolic regulation in lymphocytes bridges immunology, cancer, and metabolism research. Lymphocytes are an excellent model system to study metabolic transitions and regulation as lymphocytes are highly sensitive to changes in nutrient uptake and must maintain the capacity to rapidly and strongly upregulate cellular metabolism. By examining the selective requirements for metabolic pathways in T cell subsets and leukemia we hope to identify new approaches to treat inflammatory diseases or cancer.