cose uptake can enhance T cell function. Transgenic expression of Glut1 increased glucose uptake and metabolism in T cells, led to a larger basal cell size and hyperactivation of transgenic T cells with elevated IL2 and IFN production, and more rapid proliferation when stimulated. Over time, T cell specific Glut1 transgenic animals developed lymphadenopathy and splenomegaly, with hypergamma globulinemia and glomerular immune complex deposition at one year of age, demonstrating increased glucose metabolism can enhance lymphocyte function. Metabolic reprogramming to support lymphocyte activation, however, is not uniform and distinct stimuli promote metabolic pathways to match the needs of specific cell functions. Depending on the cytokine environment, activated CD4 T cells differentiate into inflammatory effectors, such as Th1 and Th17 cells, or immunologic suppressors, Treg. Th1 and Th17 CD4 T cells express high levels of Glut1 and depend on order UPF 1069 glycolytic flux. Treg, however, have lower levels of Glut1 expression and instead rely on mitochondrial metabolism and lipid oxidation. Macrophage M1 and M2 subsets follow a similar pattern; with inflammatory M1 macrophages being predominantly glycolytic while anti-inflammatory M2 macrophages utilize lipid oxidation. Metabolic reprogramming of activated effector T cells to favor glycolysis and lactate production is then reversed back to an oxidative phenotype at 
the conclusion of an immune J Immunol. Author manuscript; available in PMC 2015 April 15. Caro-Maldonado et al. Page 3 response, with memory CD8 lymphocytes decreasing glycolysis and instead relying on lipid oxidation. Similar to the reduced glycolysis of anergic or memory T cells, B cell activation can fail to induce glycolysis if FcRIIB is co-ligated. Tolerance inducing and immune suppressive mechanisms can, therefore, prevent or modify metabolic reprogramming. B cell tolerance mechanisms are well defined, and include apoptosis, receptor editing, and the induction of anergy. However, these tolerance mechanisms can be prevented or overridden by chronic cytokine stimulation to promote autoimmunity, such as can occur in SLE. For example, increased levels of the cytokine B Cell Activating Factor are associated with Systemic Lupus Erythematosus and transgenic BAFF overexpression to chronically expose B cells to elevated levels of BAFF leads to a spontaneous SLE-like disease in mice. Importantly, BAFF can activate the PI3K/ Akt signaling pathway and promote glucose utilization in B cells. BAFF inhibition is a PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19843186 promising new biologic therapy in SLE, yet the impact of chronic BAFF exposure on B cell metabolism and roles of altered cellular metabolism in autoimmunity are uncertain. Lymphocyte metabolism may provide a new opportunity to modulate immunity and inflammatory disease. Here we examine the regulation of B cell metabolism upon activation and the metabolic effects of anergy or chronic BAFF stimulation and autoimmunity. Surprisingly, we show that B cells are metabolically distinct from T cells, and do not switch to predominantly favor glycolysis but instead increase metabolism in a balanced fashion. Anergy and chronic BAFF overexposure led to broad and opposing changes in B cell metabolic capacity, with anergy suppressing and chronic BAFF overexposure enhancing cell metabolism. In particular, B cells from BAFF transgenic mice were primed to rapidly increase glycolysis upon stimulation. These changes were critical for B cell function, as inhibit