MetaboLightsapplication/xmlftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/Platebound_Tcell_COMBIT_pos_meta.xlsxftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/Neg_Tcell_COMBIT_neg_meta.xlsxftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/Tcell_COMBIT_pos_meta.xlsxftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/170804_Immunocult_Tcell_metadata.xlsxftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/m_mtbls926_NEG_LC-MS_metabolite_profiling_v2_maf.tsvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/m_mtbls926_POS_LC-MS_metabolite_profiling_v2_maf.tsvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/a_mtbls926_NEG_LC-MS_metabolite_profiling.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/i_Investigation.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/a_mtbls926_POS_LC-MS_metabolite_profiling.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/s_mtbls926.txtftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/expt_9_meta.csvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/expt_10_meta_1.csvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/Tcell_COMBIT_pos_meta.csvftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/files-all.jsonftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926/DERIVED_FILESftp://ftp.ebi.ac.uk/pub/databases/metabolights/studies/public/MTBLS926primaryOK2000001248Shashank Jatavmass spectrometry<p>300 μl of extraction buffer (acetonitrile:methanol:water 2:2:1) was added to frozen cell pellets (1 x 10^6 cells) on ice and allowed to stand for 30 min. Samples were vortexed then centrifuged for 10 min at 15,000 RPM. The supernatants were transferred to new vial and dried under vacuum centrifugation. Samples were resuspended with 100 μl of resuspension buffer (acetonitrile:water 5:95).</p>https://www.ebi.ac.uk/metabolights/MTBLS926Shashank Jatav.Samantha Hiemer. shiemer88@gmail.com.<p>The processing for metabolomic datasets was done through El-Maven (<a href='https://doi.org/10.5281/zenodo.2537593' target='_blank'>https://doi.org/10.5281/zenodo.2537593</a>).</p>shRNA KnockdownCRISPR KnockoutDrug PerturbationTimeActivation Protocolshashank.jatav@elucidata.io<p><strong>Primary human CD4+ T cell isolation, culture, and activation:</strong></p><p>Blood was collected from healthy human patients in accordance with IRB standards. CD4+ T cells were purified using RosetteSep isolation kit (StemCell) as per manufacturer’s protocol. Cells were cultured in RPMI supplemented with 10% heat inactivated FBS, HEPES, penicillin/streptomycin, non-essential amino acids, glutamax, and sodium pyruvate. Cells were initially activated for 72 hr on plate-bound alpha-CD3 (200 ng/ml; OKT3; BioXCell) and alpha-CD28 (200 ng/ml; 9.3; BioXCell) on goat-alpha-mouse (10 µg/ml; Jackson Immuno Research Labs) pre-coated high-binding plates (Corning Costar). After 72 hr, cells were removed from plate activation and were expanded until Day 8-12, maintained at ~1 x 10^6 cells/ml by supplementing with fresh media as required. Cells were then washed with PBS and either rested or re-activated at 0.5-1 x 10^6 cells/ml in fresh media with plate-bound alpha-CD3/alpha-CD28 (100 ng/ml each) or with soluble ImmunoCult CD3/CD28 (1:100 dilution; StemCell). Cells were treated with Rapamycin (100 nM) and/or Cyclosporin A (2 µM), or equivalent volume of DMSO during re-activation.</p><p><br></p><p><strong>Lentiviral transduction and shRNA knockdown:</strong></p><p>Lenti-X 293T (Clontech) cells were plated on poly-D-lysine (0.1 mg/ml; Sigma) coated plates at a density of 1.67 x 10^5 cells/ml. After 72 hr, cells were transfected with psPAX2 (1.5 µg), pCMV-VSV-G (0.5 µg), and pZIP-mCMV-ZsGreen-shRNA NT Control or mTOR plasmids (2 µg; Transomic) using the TransIT-LT1 transfection reagent (Mirus) as per manufacturer’s protocol. Virus was collected after an additional 72 hr and CD4+ T cells were spin infected after 48 hr of activation using undiluted virus (~1 x 10^8 IFU yielding a MOI of ~70) supplemented with polybrene (10 µg/ml; AmericanBio Inc). After an additional 24 hr of activation, the transduced CD4+ T cells were removed from activation and expanded in the presence of puromycin (1 µg/ml) until Day 8-12, maintained at ~1 x 10^6 cells/ml by supplementing with fresh media as required. Cells were then washed and activated as described above.</p><p><br></p><p><strong>CRISPR/Cas-9 knockout:</strong></p><p>Cells were activated on plate-bound α-CD3/α-CD28 as described above. Cells were removed from plate activation after 72 hr and were rested overnight at ~1 x 10^6 cells/ml. The following day the conditioned media was saved before washing the cells and resuspending in buffer T (Neon Transfection System; ThermoFisher) at 2.5 x 10^6 cells/ml. Guides targeting human mTOR and ZAP70 were designed using the Broad Institute’s online sgRNA designer (<a href='https://portals.broadinstitute.org/gpp/public/analysis-tools/sgrna-design' target='_blank'>https://portals.broadinstitute.org/gpp/public/analysis-tools/sgrna-design</a>)[1] (see Table S2 in the paper associated with this study). 5 guides per gene were synthesized by IDT and duplexed in a 1:1 ratio with Alt-R-CRISPR-Cas9-tracrRNA (IDT) as per manufacturer’s protocol. Duplexed guides were incubated with Alt-R S.p. Cas9 Nuclease (IDT) before mixing with 2.5 x 10^6 cells and electroporating using the Neon Transfection System (ThermoFisher; 100 µl tip at 1550 V, 10 ms, 3 pulses). Cells were allowed to recover for 1 hr in fresh media before adding back conditioned media in a 1:1 ratio conditioned to fresh media. Cells were expanded in the presence of IL-2 (2 ng/ml; R&amp;D) until Day 8-12, maintained at ~1 x 10^6 cells/ml by supplementing with fresh media as required. Cells were then washed and activated as described above.</p><p><br></p><p>Ref:</p><p>[1] Doench JG, Fusi N, Sullender M, Hegde M, Vaimberg EW, Donovan KF, Smith I, Tothova Z, Wilen C, Orchard R, Virgin HW, Listgarten J, Root DE. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat Biotechnol. 2016 Feb;34(2):184-191. doi: 0.1038/nbt.3437. PMID:26780180</p>MetaboLightsPublicMetabolomicsLiquid Chromatography MS - Negative (LC-MS (NEG))Liquid Chromatography MS - Positive (LC-MS (POS))<p><strong>MS parameters:</strong></p><p>120,000 resolution, AGC Target 1.0 x 10^6, Maximum IT 100 ms, Sheath Gas Flow 30, Aux Gas Flow 5, Sweep Gas Flow 5, Spray Voltage (Kv) 4.3, Capillary Temp (°C) 275, S Lens RF 70, Aux Heat Temp (°C) 250.</p>ultra-performance liquid chromatography-mass spectrometryImmunosuppressantuntargeted metabolitesT-Cell Receptor<p>10 μl of each sample was injected on our LC-HRMS system (Agilent 1290 UPLC in tandem with a Thermofisher High Field Q-Exactive) and separated using an ion-pairing chromatography.</p><p><br></p><p><strong>Positive mode:</strong></p><p>Waters Acquity 2.1 x 100 mm BEH C18, 1.7μ column heated to 50 °C. Mobile phase A – 5 mM perfluoropentanoic acid, mobile phase B – 50% Acetonitrile; flow rate: 0.4 ml/min; gradient – time 0 min = 2% B, time 0.5 = 2% B, time 10 min = 60% B, time 10.2 min = 90% B, time 12 min = 90% B, time 12.2 min = 50% B, time 14 min = 50% B, time 14.2 min = 2% B, time 18 min = 2% B.</p><p><br></p><p><strong>Negative mode:</strong></p><p>Waters Acquity 2.1 x 100mm HSS T3, 1.7μ column heated to 35 °C. Mobile phase A – 5% Methanol + 10 mM tributylamine &amp; 15 mM acetic acid, mobile phase B – Isopropyl alcohol; flow rate: 0.4 ml/min; gradient – time 0 min = 0% B, time 4 = 0% B, time 7 min = 2% B, time 12.5 min = 10% B (flow rate 0.35 ml/min), time 13 min = 10% B (flow rate 0.3 ml/min), time 17 min = 25% B (flow rate 0.2 ml/min), time 20 min = 25% B (flow rate 0.2 ml/min), time 23 min = 0% B (flow rate 0.3 ml/min), time 24 min = 0% B (flow rate 0.4 ml/min), time 29 min = 0% B (flow rate 0.4 ml/min).</p>Integrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T Cells. 10.2139/ssrn.3473264.ultra-performance liquid chromatography-mass spectrometryImmunosuppressantuntargeted metabolitesT-Cell ReceptorElucidata<p>The compound database used for processing was derived from KEGG[1] database, our final compound database consisted of all the compounds found in all of the KEGG’s reaction database. Automated peak picking feature of El-Maven was then used to get the peak intensity of all the metabolites. To get the differential expression between different cohorts metaboanalyst[2] was used (<a href='http://www.metaboanalyst.ca' target='_blank'>http://www.metaboanalyst.ca</a>). To annotate the metabolomic peaks, the mass which had least p-value in differential expression was selected. Enrichment of pathways in figure 3f was calculated using metaboanalyst.</p><p><br></p><p>Ref:</p><p>[1] Kanehisa M and Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000 Jan 1;28(1):27-30. doi:10.1093/nar/28.1.27. PMID:10592173</p><p>[2] Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, Wishart DS, Xia J. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res. 2018 Jul 2;46(W1):W486-W494. doi:10.1093/nar/gky310. PMID:29762782</p>4-hydroxybenzoic acid2'-deoxyadenosine 5'-monophosphate(R)-carnitinegamma-L-glutamylputrescine2-phospho-D-glyceric acidferulic acidN(2)-acetyl-L-ornithineglutaric acidimidazole-4-acetaldehyde2'-deoxycytosine 5'-monophosphate2-deoxy-D-riboseD-xylono-1,5-lactoneuric acidNormorphinemesaconic acidO-Succinyl-L-homoserine3',5'-cyclic AMPporphyrinacetyl dihydrogen phosphateL-glutamine2',4'-dihydroxyacetophenoneNMN zwitterioncytidine2-oxoadipic acidmandelic acidCMP-2-aminoethylphosphonatephenylacetic acidadenosine(S)-malic acid(S)-3-hydroxytetradecanoyl-CoAD-lysineD-Psicosesedoheptulose 7-phosphate1-Hydroxy-2-naphthoic acid3-sulfino-L-alanineN-carbamoylsarcosinepseudouridine 5'-phosphatebenzoatepyruvic acid1D-myo-inositol 6-phosphate(R)-malic acidN-formimidoyl-L-glutamic acidL-isoleucinehistamine2-Phenyl-1,3-propanediol monocarbamateL-methioninehomovanillic acid7H-purineitaconic acid3-Methoxytyrosinecreatinine5'-acetylphosphoadenosineD-ribulose5,6-dihydroxyindoleN-acetyl-L-alaninedihydroxyacetone phosphateD-xylulofuranoseUDP-N-acetyl-alpha-D-galactosamineADP-D-riboseL-ascorbic acid6-Mercaptopurine ribonucleoside 5'-diphosphateFMNL-glutamic 5-semialdehyde zwitterionisopyridoxalMethyl vanillate4-oxo-4-(pyridin-3-yl)butanoic acidnicotinic acid D-ribonucleotideL-gulopyranoseisocitrate(3-)4-(Methylnitrosamino)-1-(1-oxido-3-pyridinyl)-1-butanoneguanosineleucodopachromeL-4-hydroxyglutamic semialdehydetaurocyamine zwitterion5-aminolevulinic acid5-oxo-D-proline2,5-dioxopentanoic acid1-phenyl-1,2-propanedione2-Propylglutaric acidglutathione disulfideindole4-pyridoxic acidL-tryptophan1-pyrroline-2-carboxylic acid zwitterionN,N-dimethylglycine6-Thioxanthine 5'-monophosphateN(6)-(1,2-dicarboxyethyl)-AMPN-methyl-D-aspartic acidUDP-alpha-D-glucose(N(omega)-L-arginino)succinic acidribitolphosphonoacetic acidcis-aconitic acid6-acetamido-2-oxohexanoic acidD-mannopyranose 6-phosphate2'-deoxyinosine-5'-diphosphateN-methyl-L-glutamic-acid3-Carbamoyl-2-phenylpropionaldehydeadenosine 5'-monophosphate(2-)cysteic acid4-Hydroxy-1-(3-pyridinyl)-1-butanoneaspartame(2-aminoethyl)phosphonic acidADP-alpha-D-mannose3-(3-hydroxyphenyl)propanoic acidN-acetyl-L-aspartic acidtrans-3-coumaric acidanserineN-acetylneuraminic acid 9-phosphateS-(Formylmethyl)glutathione1-methyl-7H-xanthinehomocystineN-acetyl-L-glutamate(2-)precursor Z hydratemevalonic acidN-acetyl-L-methionineL-arabinitolgamma-Hydroxy-3-pyridinebutanoateindoxylL-dopaN(4)-acetyl-L-2,4-diaminobutyric acid zwitterionalpha-D-glucuronic acidN-acetyl-L-serinetrans-2-coumaric acidN-carbamoyl-beta-alanine3-(4-hydroxyphenyl)lactic acidD-ornithineIsopentenyladenineindol-3-ylacetaldehydeD-tartaric aciddTDPpyrrole-2-carboxylic acid5-acetamidopentanoic acid2-oxoglutaric acidXTPD-xylosebeta-D-fructofuranose 6-phosphatexylitolD-mannopyranoseparacetamolN-acetyl-beta-neuraminic acidL-allothreoninefumaric acid(R)-5-diphosphomevalonic acidN-glycoloyl-beta-neuraminic acidL-homoserineochratoxin A2,3-diketogulonic acidcytidine 5'-monophosphate9H-xanthineestrone 3-O-(beta-D-glucuronide)(2R,3R)-2,3-dihydroxy-3-methylpentanoic acidD-ribulose 5-phosphatepiperidineS-carboxymethyl-L-cysteineneopterinbeta-D-fructofuranose 1,6-bisphosphatemalonic acidD-tagatofuranose 1,6-bisphosphateNADN-acetyl-D-mannosamine3-(4-oxo-4,5-dihydro-1H-imidazol-5-yl)propanoic acid5-amino-6-(D-ribitylamino)uracilP(1),P(4)-bis(5'-adenosyl) tetraphosphatealpha-ribazoleL-tyrosineN(2)-formyl-N(1)-(5-phospho-D-ribosyl)glycinamidetrans-4-hydroxy-L-prolineS-adenosyl-L-methionine3'-UMPN(2)-acetylglutamineGTPinosinebeta-D-fructofuranose 1-phosphatesarcosineN(6),N(6),N(6)-trimethyl-L-lysinevanillylamine[1-(5-phosphoribosyl)imidazol-4-yl]acetic acidN(2)-succinyl-L-ornithineSubaphyllinN-carbamoyl-L-aspartic acidL-xylonic acidD-tryptophan(6R)-L-erythro-6,7-dihydrobiopterinL-tartaric acidhypoxanthine2-Hydroxyfelbamate1-phenylethanol3-hydroxybenzoic acidD-glutamic acidL-asparagineenol-phenylpyruvate(-)-epigallocatechin 3-gallateD-glucuronic acid 1-phosphatetheophyllineD-tagatofuranose 6-phosphatedoxifluridine5,6-epoxyretinoic acidcarglumic acidcis-4-hydroxy-D-prolinegamma-aminobutyric acid(S)-lactic acid(1-Ribosylimidazole)-4-acetateCarbamazepine-o-quinoneGDP-alpha-D-glucoseL-gulonic acidN-formyl-L-kynurenineGDP-alpha-D-mannose5-amino-2-oxopentanoic acid5-methylcytosinesuccinic acidD-arabinitol4-[(Hydroxymethyl)nitrosoamino]-1-(3-pyridinyl)-1-butanoneL-kynurenine(R)-octopamine6-amino-2-oxohexanoic acidalpha-D-galactose 1-phosphate4-KetocyclophosphamideO-phosphoethanolaminebeta-D-fructofuranose 2-phosphateL-alanineADP alpha-D-glucosideglyceraldehyde 3-phosphateL-phenylalaninemelphalanN-acetylserotonin2-ammonioprop-2-enoatetrans-resveratrol(R)-S-lactoylglutathioneNADH3-methyl-2-oxobutanoic acid4-(L-gamma-glutamylamino)butanoic acid1-methylpyrrolinium5-Phenyl-1,3-oxazinane-2,4-dioneoleoyl-CoA1-methyladenosineadenosine 5'-monophosphatealpha-ribazole 5'-phosphate1-aminocyclopropanecarboxylic acidD-glucopyranose(R)-pantolactoneL-serinecordysinin B2-hydroxyestroneall-trans-18-hydroxyretinoic acid1D-myo-inositol 1-phosphate6-O-phosphono-D-glucono-1,5-lactoneN-acetylputrescineD-glucurono-6,3-lactoneUDP-N-acetyl-alpha-D-glucosamineL-asparaginate4-hydroxyphenylacetic acidtrans-Cyclohexane-1,2-diolnicotinamidedADP2-hydroxyglutaric acidtrans-aconitic acidL-histidineN,N-dimethylethanolamine phosphateN-acetyl-L-glutamic acidbeta-L-arabinose 1-phosphate4-hydroxy-1-pyrroline-2-carboxylic acidtrans-3-hydroxy-L-proline5-(2-hydroxyethyl)-4-methylthiazolep-cresolphosphoenolpyruvic acidcaffeic acidthiamine(1+)CDP-ethanolamineputrescinealpha-D-galactosyl-(1->3)-1D-myo-inositolspermidineD-cysteinegamma-Glutamyl-Se-methylselenocysteinetaurineurocanic acid3-methylxanthineL-cystathionineguaninehypotaurine(R)-noradrenaline4-acetamidobutanoic acidDechloroethylcyclophosphamideO-acetyl-L-serine(4R,5S)-dethiobiotinGlyceraldehyde 3-phosphate diethyl acetalL-rhamnopyranoseS-methyl-5-thio-D-riboseinosine 2'-phosphateglutathione7-aminomethyl-7-deazaguanine7-Methyluric acidD-prolineCMP-N-acetyl-beta-neuraminic acidUDP-D-galactoseimidazol-4-ylacetic aciduridine(3S)-3,6-diaminohexanoic acidtrichloroepoxyethaneadenylyl selenate4-hydroxy-2,6-dimethylanilineL-ornithine1,7-dimethylxanthineL-xylulosemyo-inositol 1,3-bisphosphate2-phenylacetamideN-methylhydantoinD-threonic acidD-glucitolmethylmalonic acidgalactitolN-succinyl-L-glutamic 5-semialdehyde5-(3-Pyridyl)-2-hydroxytetrahydrofuran(Z)-but-2-ene-1,2,3-tricarboxylic acidisoniazideN(6)-acetyl-L-lysineN-acetyl-alpha-D-mannosamine 6-phosphatedUMPalpha-D-galactose2-DechloroethylifosfamidevalacyclovirD-xylulose 5-phosphateethylmalonic acid(S)-3-aminoisobutyric acid zwitterionketo-D-fructose 1,6-bisphosphateGDP-6-deoxy-alpha-D-mannoseL-argininetrans-5,6-Dihydro-5,6-dihydroxy-7,12-dimethylbenz[a]anthracenealpha,alpha-trehalose 6-phosphate1D-myo-inositol 3,4-bisphosphate3-hydroxy-3-methylglutaric acidD-ribofuranosethymidineL-cysteine2'-deoxyguanosine 5'-monophosphate4-Hydroxy-5-phenyltetrahydro-1,3-oxazin-2-oneN-acetyl-L-cysteine2'-deoxyadenosine5'-deoxyadenosine2',3'-cyclic GMPL-fuculosecreatine2'-deoxycytidineL-aspartic acid6-lactoyl-5,6,7,8-tetrahydropterinkynurenic aciddTMP3-hexaprenyl-4,5-dihydroxybenzoic acidAlcophosphamideAICA ribonucleotide4-(Methylnitrosamino)-1-(3-pyridyl-N-oxide)-1-butanol5-oxoprolinearabinose5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamideL-citrullinemethionine S-oxidecytosine2'-deoxyguanosine4,5-dioxopentanoic acidL-cystineN-benzoylglycineuridine 5'-monophosphate(4-hydroxy-3-methoxyphenyl)acetaldehyde2-Amino-3-methylbenzoateL-glutamic acidalpha-D-glucose 1,6-bisphosphateD-glucopyranose 6-phosphatealpha-lactoseL-threoninezidovudinegeranyl diphosphateN-formyl-L-glutamic acid1-methyluric acidxanthurenic acidcitraconic acidN-acetyl-L-phenylalaninemaleic acid5'-xanthylic acidL-gamma-glutamyl-L-cysteineisomaltosedihydroxyfumaric aciddopaminelactose 6'-phosphateN-phosphocreatinemethyl beta-D-glucopyranoside7,9-dihydro-1H-purine-2,6,8(3H)-trione2-aminomuconic acid(4-hydroxyphenyl)pyruvic acidL-alpha-aminobutyric acid(R)-pantothenateformyl-5-hydroxykynurenamine1,2-dihydroxy-5-(methylthio)pent-1-en-3-oneestronescyllo-inositol(4-hydroxyphenyl)acetaldehydepyridoxal 5'-phosphateIDP(3S,5S)-3,5-diaminohexanoic acid3-hydroxy-L-kynurenineN-[(R)-4-phosphopantothenoyl]-L-cysteinecitramalic acidzalcitabineerythro-5-hydroxy-L-lysine4-hydroxybenzaldehydealpha,alpha-trehalose(R)-adrenaline(2-hydroxyphenyl)acetic acid5-hydroxykynurenineD-ribofuranose 5-phosphatealpha-D-glucoseguanidinoacetic acidagmatine4-Hydroxy-4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone(R)-lactic acidL-gamma-glutamyl phosphatespermine1D-myo-inositol 1,4-bisphosphate5,6,7,8-tetrahydropterin-6-carboxylic acidL-allysine zwitterionbutane-2,3-dioneN-acetyl-D-glucosamine(S)-3-phenyllactic acidpyridoxamine 5'-phosphate2-oxobutanoic acidallantoinphosphoric acidpantetheine 4'-phosphate15-deoxy-Delta(12,14)-prostaglandin J23-Hydroxymonoethylglycinexylidide(R)-lipoic acidN(2)-acetyl-L-lysineN-formyl-L-methionineporphobilinogen2,3-bisphospho-D-glyceric aciddTTPD-glutamine4-guanidinobutanoic acidbeta-alanyl-L-arginine5-amino-1-(5-phospho-beta-D-ribosyl)imidazoleN-acetyl-D-glucosamine 6-phosphateL-leucineglycerylphosphorylethanolamineerythro-5-phosphonooxy-L-lysineglycerol 2-phosphate5-fluorouridine3-nitro-L-tyrosine(5-hydroxyindol-3-yl)acetic acid4-KetoifosfamideGDP-L-fucosefolic acidmolybdopterin adenine dinucleotideguanosine 5'-monophosphate1-Nitro-5,6-dihydroxy-dihydronaphthalene(R)-3-aminoisobutyric acid zwitterionFAD3-amino-3-(4-hydroxyphenyl)propanoic acid5,6,7,8-tetrahydrobiopterinAlcoifosfamidetrans-3,4-Dihydro-3,4-dihydroxy-7,12-dimethylbenz[a]anthraceneLL-2,6-diaminopimelic acidcodeineL-arabinopyranosedyspropterin3-methoxyanthranilic acidL-homocarnosineuracilmelatoninL-rhamnulose2-acetamido-5-oxopentanoic acid(R)-2,3-dihydroxy-3-methylbutanoic acidO-phospho-L-serineacetoacetic acidthyminepyridoxallactosamine5-hydroxy-L-tryptophanS-adenosyl-L-homocysteineaflatoxin Q1tryptopholmyo-inositolGDPophthalmic aciddimethylmaleic aciddihydroorotic acid16alpha-hydroxyestrone5-acetamido-6-formamido-3-methyluracilorotic acidD-aspartic acidbeta-D-glucosamine 6-sulfatealpha-[3-[(Hydroxymethyl)nitrosoamino]propyl]-3-pyridinemethanolD-gluconatetetracycline zwitterion4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol glucuronideL-allopyranoseN-acetylglycine7,8-dihydroneopterin2',3'-cyclic CMPtyramineN-acetyl-alpha-D-glucosamine 1-phosphatebeta-D-glucose 6-phosphateallyl isothiocyanateD-glucopyranose 1-phosphatetrans-4-coumaric acid3'-phospho-5'-adenylyl sulfateallantoic acidMaleamate8,9-dihydro-8-(S-glutathionyl)-9-hydroxyaflatoxin B12-aminoisobutyric acidtrans-cinnamic acidN-hydroxynaphthalen-1-aminecitric acidphenolbeta-D-glucosepantothenic acid5,6-dihydrouracilalpha-maltoseketo-D-fructose 6-phosphate3-Methoxy-4-hydroxyphenylethyleneglycol2-methyl-3-oxopropanoic acid(S)-2-acetyl-2-hydroxybutanoic acidD-argininebenzylpenicillinketo-phenylpyruvic acidAflatoxin B1 diolpyridoxinefloxuridine4-acetamidobutanalphenylacetaldehyde3-hydroxyphenylacetateN-methylnicotinic acidnonanedioic acidD-serine1-methyl-4-imidazoleacetic acidalpha-D-ribose 1-phosphate3-aminoisobutyric acidBisnorbiotinD-alanineglycerol 1-phosphateindole-3-acetonitrileD-2-aminopentanoic acidN-ribosylnicotinamidebeta-D-fructofuranose 2,6-bisphosphatebeta-alanineall-trans-4-hydroxyretinoic acidglutaurinesulfonyldimethane(5S)-5-amino-3-oxohexanoic acid zwitteriondihydrourocanic acid3-(2-hydroxyphenyl)propanoic acidsuccinic semialdehydephenylacetylglycineN-methylethanolamine phosphate2-deoxy-D-ribose 5-phosphateaflatoxin B1 exo-8,9-epoxide4-(2-aminophenyl)-2,4-dioxobutanoic acid2'-deoxyinosine-5'-monophosphate(S)-methylmalonaldehydic acidaflatoxin M13-phenyllactic acid1D-myo-inositol 4-phosphatetrans-urocanic acidN-4-hydroxyphenylacetylglutamic acidGlyceric acid 1,3-biphosphateL-dopaquinone(R)-2-hydroxyglutaric acid2',3'-cyclic AMPketo-D-tagatose5-amino-6-(5-phospho-D-ribitylamino)uracilD-mannitolN-acetylcitrullineUDP2-oxobutanoate3',5'-cyclic GMPL-sorbose 1-phosphateglycine betainebiotin5-oxo-L-prolinelauroyl-CoAL-pipecolic acidsedoheptulose 1,7-bisphosphatesucroseIMP2-aminomuconic 6-semialdehyde5'-S-methyl-5'-thioadenosine2'-deoxyinosinemelibiose4-methylthio-2-oxobutanoic acidL-Lyxonate2-amino-3-phosphonopropanoic acid2-[(2-acetamido-3-carboxy-1-oxopropyl)amino]pentanedioic acidCDP-choline4-aminobenzoic acidO-phosphoserineNormetanephrineD-fructoseD-glucosaminep-Hydroxyfelbamate7-methylxanthineGDP-4-dehydro-6-deoxy-alpha-D-mannose(3R,5S)-1-pyrroline-3-hydroxy-5-carboxylic acidbeta-alanyl-L-lysine2'-deoxyuridineanthranilic acidbiotin sulfoneN(tele)-methyl-L-histidinealdehydo-D-galacturonic acidL-prolineUDP-N-acetyl-D-mannosamine5-aminopentanoic acidD-tagatose2-aminoadipic acid(R)-rosmarinic acidD-mannose 1-phosphateindole-5,6-quinoneN'-acetylisoniazid3'-AMP2-Hydroxy-2-ethylsuccinic acidcarnosine2-oxoglutaramic acidadenineL-valine3-phosphoglyceric aciderythritolN-acetyl-beta-alanine0.00.00.0154476475757838320.00.01248metabolights~624chebi~624biochemical pathways, projections, l(3)rK137, TC-NER, Metabolic Process, R*-(E)])-Cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N, Glukose, Aminosaeure, Metabolic Concepts, Metabonomic, Receptors, Amino acid, Monohydrate, Metabonomics, (DL)-Isomer, ciclosporinum, ctps, CG17228, 10, 1135/09, 11, 12, 1135/07, 13, 14, 15, 16, 17, CyA-NOF, 18, 19, diseases, Carbon-12, CTPS, Dextrose, 0451/09, symptoms, Concepts, 1, diseases and disorders, 4, 5, Metabolism Concept, 7, 8, Phenomenon, 9, CsA-Neoral, immature T cell, 20, 22, 23, C, increased, 25, 0244/09, 26, sdu, human disease, 28, amino acids, 29, ctps1-b, enzymes, Biology, MUB3_18, transcription-coupled NER, Cyclosporine, (R-[R*, catabolism, T Cell Antigen Receptor, Cyclo(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-((3R, DROPROSA, metabolic process resulting in cell growth, PMNC, l(3)j6E2, MUB3.18, ASL, Asl, DL-glucose, 671/2, glucose, 4-dimethyl-L-2-aminooctanoyl)-L-2-aminobutanoyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methylleucyl), OL 27-400, anon-WO0172774.90, 0320/10, DMPROSPER, medicine, papilla, signaling process, Carbon, anon-WO0172774.92, Adenylosuccinase, biotransformation, Homo sapiens disease, Ctps, Catabolism, single organism signaling, 3R, close to, 7-didehydro-3-hydroxy-N, screening, Cyclosporin, anatomical protrusion, OL 27400, Adl, cyclosporin A, Process, l(3)rO534, T-Cell Receptor, Pro, PRO, T-Cell Antigen, Aminokarbonsaeure, ctps-b, metabolism resulting in cell growth, transcription-coupled repair, lamina, flanges, 24-tetrakis(2-methylpropyl)-3, PMN cell, CYS, results, alpha-amino carboxylic acids, 4R, Vitreous, PROS-1, Antigen Receptor, Antibiotic S 7481F1, PROS-2, Cyclosporine A, T Cell Receptor, T-Cell, pro, 1316/02, shelf, Diseases, BcDNA:HL08040, secretion, (alpha-D)-Isomer, and GLY protein 2, ASase, glucose metabolism, D-Glucose, Amino Acid, Acid, T-cell, and GLY protein 1, Amino acids, Voila, Cyclosporin A, 6C, shelves, 0664/07, 1167/13, signs, T-lymphocyte, Ciclosporin, TAF[[II]], projection, ridge, human, SmokTcr, white blood cell, disease, Vitreous Carbon, T cell, D Glucose, spine, carbonium, Biocatalyst, Dominant negative form of Smok, medical condition., l(1)16Fg, T Cell, T-cell receptor complex, Acids, 0989/01, Glucose Monohydrate, accessory, polymorphonuclear cell, pds, gluco-hexose, other disease, biological signaling, human being, Glucose, Processes, lamellae, Biocatalysts, 4-dimethyloct-6-enoyl-L-2-aminobutanoyl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine], Aminocarbonsaeure, CG6854, carbon, alpha-amino acid, Metabolic Processes, 0763/13, process of organ, supernumerary, Sandimmun Neoral, l(3)10419, protrusion, Responder protein Smok-Tcr, lamella, dmTAF8, 4.3.2.2, DmelCG17228, Metabolism, 2510006M18Rik, HL-VIII, 21-bis(propan-2-yl)-1, CyA NOF, AMPS, disease or disorder, anon-WO0140519.15, F15E12.6, CsA Neoral, Prosp, Metabolomic, Metabolism Phenomena, 11-cyclo[L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-(E)-(2S, study, PROS, F15E12_6, 0585/13, CG2919, ciclosporin, CG7128, Metabolic Concept, ridges, man, ASASE, OL 27 400, T-Cell Receptors, l(3)rH013, non-neoplastic, prod, Kohlenstoff, Prodos, Enzyme, drugs, mature T cell, disorder, TAF, 0563/18, 31-undecaazacyclotritriacontane-2, Neoral, laminae, Anhydrous, 6E)-6, Antigen Receptors, 21-diisopropyl-1, 0671/02, l(3)j12C8, 4-dimethyl-L-2-amino-6-octenoyl-L-alpha-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl), 32-undecone, data, findings, immune cell, T-Cell Antigen Receptor, (beta-D)-Isomer, degradation, T-lymphocyte receptor complex, anatomical process, drug, disorders, enzyme activity, alpha-amino acids, ciclosporina, carbone, Cell, l(3)rJ806, 28-nonamethyl-6, Concept, Metabolic Phenomena, Pros, carbono, near to, T Cell Antigen, 28-nonamethyl-1, Metabolism Concepts, l(3)rL433, 2.7.11.1, ciclosporine, DmelCG6854, l(3)rI160, TCR complex, 0441/16, Systems, Phenomena, TFIID, condition, 30-ethyl-33-[(4E)-1-hydroxy-2-methylhex-4-en-1-yl]-1, metabolism, T lymphocyte, Ctps1, flange, ATCMPG1, MET, organ process, Metabolic Phenomenon, ATCMPG2, T lymphocyte receptor complex, 30-ethyl-33-[(4E)-1-hydroxy-2-methylhex-4-en-1-yl]-6, Tcr, TCR, ASAL, multicellular organism metabolic process, leucocyte, biodegradation, Metabolic, IMD24, 24-tetraisobutyl-3, increased number, DmelCG2919, cellular glucose metabolic process, Amino, Anhydrous Dextrose, signalling, Carbon 12, l(3)rK204, processes, process, present in greater numbers in organism, single-organism metabolic process, DmelCG7128, signalling process, Sandimmune, mecD, approaches, T Cell Receptors, vicinity of, T-Cell Antigen Receptors, Sandimmun, processus, Gengraf, CsANeoral, Receptor, TAF8, 4R)-2-amino-3-hydroxy-N, Anabolism, GlcMetabonomic, Cell., Metabonomics, human being, Metabolomic, man, activation, humanfalseIntegrated Metabolomic and Transcriptomic Profiling Reveals Novel Activation-Induced Metabolic Networks in Human T cells<p>The targeting of metabolic pathways is emerging as an exciting new approach for modulating immune cell function and polarization states. In this study, carbon tracing and systems biology approaches integrating metabolomic and transcriptomic profiling data were used to identify adaptations in human T cell metabolism important for fueling pro-inflammatory T cell function. Results of this study demonstrate that T cell receptor (TCR) stimulation leads to a significant increase in glucose and amino acid metabolism that trigger downstream biosynthetic processes. Specifically, increased expression of several enzymes such as CTPS1, IL4I1, and ASL results in the reprogramming of amino acid metabolism. Additionally, the strength of TCR signaling resulted in different metabolic enzymes utilized by T cells to facilitate similar biochemical endpoints. Furthermore, this study shows that cyclosporine represses the pathways involved in amino acid and glucose metabolism, providing novel insights on the immunosuppressive mechanisms of this drug. To explore the implications of the findings of this study in clinical settings, conventional immunosuppressants were tested in combination with drugs that target metabolic pathways. Results showed that such combinations increased efficacy of conventional immunosuppressants. Overall, the results of this study provide a comprehensive resource for identifying metabolic targets for novel combinatorial regimens in the treatment of intractable immune diseases.</p>2024-04-032019-04-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