E, which supports mitochondrial metabolism through glutaminolysis. The transcription factor myc

E, which supports mitochondrial metabolism through glutaminolysis. The transcription factor myc is necessary for this increased mitochondrial flux. Pharmacologic inhibition of mitochondrial oxidative phosphorylation or glycolysis in vitro diminishes T cell proliferation indicating that mitochondrial metabolism and glycolysis support T cell proliferation. However, glycolysis but not mitochondrial metabolism is dispensable for T cell activation and production of the cytokine IL-2 prior to proliferation. In fact, mitochondrial metabolism was found to be required for T cell activation through generation of mitochondrial ROS necessary for optimal activity of NFAT, NF-KB and proximal TCR signaling. It is known that mitochondrial localization to the immune synapse is required for T cell activation, likely for efficiency of both calcium and ROS signals. Future studies will more clearly define the mitochondrial ROS molecular target in T cell activation. The notion that mitochondrial metabolism is necessary for T cell activation is further supported by the observations that chronically activated T cells isolated from mouse model of lupus are dependent on Immunity. Author manuscript; available in PMC 2016 March 17. Weinberg et al. Page 10 mitochondrial metabolism and peripheral blood lymphocytes from patients with lupus have increased mitochondrial metabolism and ROS production. Differential metabolic pathways regulate CD4+ T cell differentiation Once activated, T cells differentiate into different effector T cell subsets ranging from pro-inflammatory T helper 1, Th17 and Th22 cells to suppressive regulatory T cells to curtail infection. Traditionally, these subsets have been classified by specific transcription factor activation. Emerging data indicate that these different T cell subsets have distinctive metabolic phenotypes that can promote T cell subset differentiation. Perhaps the best-studied subsets are Treg and Th17 cells, which have different metabolic profiles that are essential to establish their phenotype. Tregs have elevated levels of oxidative phosphorylation and decreased MedChemExpress 139504-50-0 glycolytic flux compared to Th17 cells. This increased mitochondrial metabolism in Tregs was found to be due to increased AMPKdependent fatty acid oxidation. Pharmacologically attenuating fatty acid oxidation by etomoxir impaired Treg differentiation but did not affect other CD4 helper subsets in vitro. By contrast, Th17 cells engage in de novo fatty acid synthesis that is necessary for the Th17 phenotype. Pharmacologic and genetic inhibition of the enzyme acetyl-CoA carboxylase 1, the enzyme that catalyzes the first step of de novo fatty acid synthesis, impaired Th17 cell differentiation and promoted Tregs in vitro and in vivo as well as attenuated EAE in mice. It is presently not clear why fatty acid oxidation versus synthesis appears to be a checkpoint in the T cell fate decision between Treg and Th17 cells. Increased glycolytic metabolism in Th17 cells also appears to be important to maintaining their Th17 lineage state. Pharmacological inhibition of glucose metabolism by administering Chebulinic acid chemical information 2-deoxyglucose attenuated Th17 cell development and interestingly promoted Treg cell development and diminished pathology in a Th17-dependent experimental autoimmune encephalomyelitis . The increase in glycolysis observed in Th17 cells is due to an increase in HIF-1, and mice with T cells deficient in HIF-1 display diminished Th17 cells, increased Treg cells, and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850718,22102576 resistance to EAE.E, which supports mitochondrial metabolism through glutaminolysis. The transcription factor myc is necessary for this increased mitochondrial flux. Pharmacologic inhibition of mitochondrial oxidative phosphorylation or glycolysis in vitro diminishes T cell proliferation indicating that mitochondrial metabolism and glycolysis support T cell proliferation. However, glycolysis but not mitochondrial metabolism is dispensable for T cell activation and production of the cytokine IL-2 prior to proliferation. In fact, mitochondrial metabolism was found to be required for T cell activation through generation of mitochondrial ROS necessary for optimal activity of NFAT, NF-KB and proximal TCR signaling. It is known that mitochondrial localization to the immune synapse is required for T cell activation, likely for efficiency of both calcium and ROS signals. Future studies will more clearly define the mitochondrial ROS molecular target in T cell activation. The notion that mitochondrial metabolism is necessary for T cell activation is further supported by the observations that chronically activated T cells isolated from mouse model of lupus are dependent on Immunity. Author manuscript; available in PMC 2016 March 17. Weinberg et al. Page 10 mitochondrial metabolism and peripheral blood lymphocytes from patients with lupus have increased mitochondrial metabolism and ROS production. Differential metabolic pathways regulate CD4+ T cell differentiation Once activated, T cells differentiate into different effector T cell subsets ranging from pro-inflammatory T helper 1, Th17 and Th22 cells to suppressive regulatory T cells to curtail infection. Traditionally, these subsets have been classified by specific transcription factor activation. Emerging data indicate that these different T cell subsets have distinctive metabolic phenotypes that can promote T cell subset differentiation. Perhaps the best-studied subsets are Treg and Th17 cells, which have different metabolic profiles that are essential to establish their phenotype. Tregs have elevated levels of oxidative phosphorylation and decreased glycolytic flux compared to Th17 cells. This increased mitochondrial metabolism in Tregs was found to be due to increased AMPKdependent fatty acid oxidation. Pharmacologically attenuating fatty acid oxidation by etomoxir impaired Treg differentiation but did not affect other CD4 helper subsets in vitro. By contrast, Th17 cells engage in de novo fatty acid synthesis that is necessary for the Th17 phenotype. Pharmacologic and genetic inhibition of the enzyme acetyl-CoA carboxylase 1, the enzyme that catalyzes the first step of de novo fatty acid synthesis, impaired Th17 cell differentiation and promoted Tregs in vitro and in vivo as well as attenuated EAE in mice. It is presently not clear why fatty acid oxidation versus synthesis appears to be a checkpoint in the T cell fate decision between Treg and Th17 cells. Increased glycolytic metabolism in Th17 cells also appears to be important to maintaining their Th17 lineage state. Pharmacological inhibition of glucose metabolism by administering 2-deoxyglucose attenuated Th17 cell development and interestingly promoted Treg cell development and diminished pathology in a Th17-dependent experimental autoimmune encephalomyelitis . The increase in glycolysis observed in Th17 cells is due to an increase in HIF-1, and mice with T cells deficient in HIF-1 display diminished Th17 cells, increased Treg cells, and PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19850718,22102576 resistance to EAE.