Upon activation, conventional T (Tconv) cells undergo an mTOR-driven glycolytic switch. Regulatory T (Treg) cells reportedly repress the mTOR pathway and avoid glycolysis. However, here we demonstrate that human thymusderived (t)Treg cells can become glycolytic in response to tumor necrosis factor receptor 2 (TNFR2) costimulation. This costimulus increases proliferation and induces a glycolytic switch in CD3-activated tTreg cells, but not in Tconv cells. Glycolysis in CD3/TNFR2-activated tTreg cells is driven by PI3-kinase/mTOR signaling and supports tTreg cell identity and suppressive function. Contrary to glycolytic Tconv cells, glycolytic tTreg cells do not show net lactate secretion and shuttle glucose-derived carbon into the tricarboxylic acid cycle. Ex vivo characterization of blood-derived TNFR2 high CD4 + CD25 high CD127 low effector T cells, which were FOXP3 + IKZF2 + , revealed an increase in glucose consumption and intracellular lactate levels, identifying them as glycolytic tTreg cells. Our study links TNFR2 costimulation in human tTreg cells to metabolic remodeling, providing an additional avenue for drug targeting.receptor 2 (TNFR2, TNFRSF1B, CD120b) costimulation in tTreg and Tconv cells. TNFR2 was previously shown to be important for Treg cell responses and protection against autoimmunity in human and mouse 30,31 and is considered a clinical target for selective Treg expansion or inhibition in transplant rejection, autoimmunity, or cancer 9, 10 . We here report that CD3-activated tTreg cells selectively respond to TNFR2 costimulation by proliferation and a PI3K/mTOR-driven glycolytic switch that is important for tTreg cell identity and function. We also identify unique elements of the glycolytic program in tTreg cells and validate our findings in tTreg cells directly isolated from human blood. RESULTS A novel strategy allows for stable human Treg cell expansion in the absence of rapamycinHuman Treg cells occur in low frequency in the blood and therefore, expansion protocols are used for clinical application 32 . In such protocols, Treg cells are flow cytometrically sorted and expanded in presence of the mTOR inhibitor rapamycin that selectively inhibits proliferation of contaminating Tconv cells 12 . However, since rapamycin affects many aspects of metabolism, these expansion protocols are not suitable to generate Treg cells for metabolic studies. Also, such cultures may still be contaminated with pTreg cells that can convert back to Tconv cells and confound data interpretation. We therefore employed a novel method to purify stable human tTreg cells, based on the marker glycoprotein (GP)A33 33 . Among CD4 + T cells, naïve Tconv cells were purified by flow cytometry on the basis of a CD25 low CD127 high CD45RA + GPA33 int phenotype and naïve tTreg cells on the basis of a CD25 high CD127 low CD45RA + GPA33 high phenotype (Extended Data Figure 1a). Phenotypic analysis of these populations indicated that the naïve tTreg cells could be discriminated from Tconv cells as previously defined 34 by expressi...
The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics. Furthermore, CD37-negative lymphomas selectively deplete palmitate from serum in mouse studies. Mechanistically, CD37 inhibits the FA transporter FATP1 through molecular interaction. Consequently, deletion of CD37 induces uptake and processing of exogenous palmitate into energy and essential building blocks for proliferation, and inhibition of FATP1 reverses this phenotype. Large lipid deposits and intracellular lipid droplets are observed in CD37-negative lymphoma tissues of patients. Moreover, inhibition of carnitine palmitoyl transferase 1 A significantly compromises viability and proliferation of CD37-deficient lymphomas. Collectively, our results identify CD37 as a direct gatekeeper of the FA metabolic switch in aggressive B-cell lymphoma.
IntroductionSwine dysentery caused by Brachyspira hyodysenteriae is a production limiting disease in pig farming. Currently antimicrobial therapy is the only treatment and control method available.ObjectiveThe aim of this study was to characterize the metabolic response of porcine colon explants to infection by B. hyodysenteriae.MethodsPorcine colon explants exposed to B. hyodysenteriae were analyzed for histopathological, metabolic and pro-inflammatory gene expression changes.ResultsSignificant epithelial necrosis, increased levels of l-citrulline and IL-1α were observed on explants infected with B. hyodysenteriae.ConclusionsThe spirochete induces necrosis in vitro likely through an inflammatory process mediated by IL-1α and NO.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-017-1219-6) contains supplementary material, which is available to authorized users.
Upon antigen-specific T Cell Receptor (TCR) engagement, human CD4+ T cells proliferate and differentiate, a process associated with rapid transcriptional changes and metabolic reprogramming. Here, we show that generation of extra-mitochondrial pyruvate is an essential step for acetyl-CoA production and subsequent H3K27ac-mediated epigenome remodeling. In contrast, neither acetate/ACSS2 nor citrate/ACLY metabolism are required for activation-induced transcriptional changes. Furthermore, T cell activation results in the nuclear translocation of PDC and its association with both the p300 acetyltransferase and histone H3K27ac. These data support tight integration of metabolic and histone-modifying enzymes, allowing metabolic reprogramming to fuel CD4+ T cell activation. Targeting this pathway may provide a novel therapeutic approach to specifically regulate antigen-driven T cell activation.
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