1、Tcells have an important function in the pathogenesis of systemic lupus erythematosus(SLE)by instigating and amplifying the inflammatory process through direct contact with other immune cells in primary or secondary lymphoid organs,through secreting pro-inflammatory cytokines or through mediating di
2、rect effects on target tissues.Many aberrations in the distribution and func-tion of Tcell subsets have been described in patients with SLE and have been linked to the immunopathogenesis of SLE(as reviewed elsewhere13).Multiple studies have identified biochemical and molecular abnormalities in Tcell
3、s,including a number of metabolic disturbances4,5,that might explain their aberrant phenotypes in patients with SLE and in lupus-prone mice.Pioneering studies have shown the importance of altered metabolic pathways in the development of aber-rant Tcell function in patients with SLE5 and have shed li
4、ght on how molecules previously linked to distinct immune cell functions can control metabolic enzymes6.However,our understanding of the metabolic control of normal Tcell function is incomplete,and the abil-ityof metabolic enzymes to control Tcell function under autoimmune conditions is largely unex
5、plored.In this Review,we first describe new developments in our understanding of the metabolic control of Tcells and the unique requirements that have emerged for the differentiation of each Tcell subset.Subsequently,we review the current understanding of the control of Tcell function by metabolic p
6、rocesses in patients with SLE.We emphasize the biochemical and molecular links between established immune molecules and the expres-sion of metabolic enzymes and highlight potential future therapeutic targets.Tcell metabolismCells require energy for survival and function,and the processing of nutrien
7、ts through distinct metabolic pro-cesses produces ATP to meet these energy requirements.The metabolic pathways of Tcells,as with other cells,are affected by the availability of nutrients such as glucose,glutamine and fatty acids(Fig.1),and nutrient availabil-ity dictates both the activation and func
8、tion of immune cells.Glucose is involved in both glycolysis and oxidative phosphorylation.Glycolysis takes place in the cytoplasm and converts glucose to pyruvate(generating two mole-cules of ATP),which is converted to either lactate(in the cytoplasm)or acetyl coenzyme A(acetyl-CoA)(inthe mitochondr
9、ia).Acetyl-CoA subsequently enters the tricarboxylic acid(TCA)cycle and produces ATP(36 molecules)via oxidative phosphorylation.Thus,glucose metabolism via both glycolysis and oxidative phosphorylation generates energy(at a faster or slower pace,respectively).In addition to glucose metabolism,immune
10、 cells can utilize the TCA cycle machinery to Tcell metabolism:new insights in systemic lupus erythematosus pathogenesis and therapyAmirSharabi1,2,3*and GeorgeC.Tsokos 1*Abstract|Tcell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupu
11、s erythematosus(SLE).Each Tcell subset function(such as effector,helper,memory or regulatory function)is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes.The activity of these enzymes or nutrient transporters influences the differenti
12、ation and function of Tcells in autoimmune responses.Data are increasingly emerging on how metabolic processes control the function of various Tcell subsets and how these metabolic processes are altered in SLE.Specifically,aberrant glycolysis,glutaminolysis,fatty acid and glycosphingolipid metabolis
13、m,mitochondrial hyperpolarization,oxidative stress and mTOR signalling underwrite the known function of Tcell subsets in patients with SLE.A number of medications that are used in the careof patients with SLE affect cell metabolism,and the development of novel therapeutic approaches to control the a
14、ctivity of metabolic enzymes in Tcell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases.1Department of Medicine,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA.2Clinical Microbiology&Immunology,Sackler Faculty of
15、Medicine,Tel-Aviv University,Tel-Aviv,Israel.3Rheumatology Institute,Rabin Medical Center,Petach-Tikva,Israel.*e-mail:isharabiamir ;gtsokos bidmc.harvard.eduhttps:/doi.org/10.1038/s41584-019-0356-xReviewsNature reviews|Rheumatologygenerate energy by metabolizing glutamine through glutaminolysis or f
16、atty acids through-oxidation.In addition to the generation of energy,various molecules of the TCA cycle serve as precursors to synthesize lipids,nucleic and nonessential amino acids and other important molecules.Tcell activation.Tcells belong to the adaptive immune system and are central to the deve
17、lopment of imm uneres-ponses to foreign antigens and in the case of loss of tolerance,to self-antigens.Naive Tcells utilize nutrients for their maintenance and homeostasis.Upon engage-ment of the Tcell receptor(TCR),Tcells adopt an anabolic metabolism phenotype to enable the rapid shift-ing from qui
18、escence to activation,proliferation and the acquisition of effector functions and increase the mito-chondrial mass for the energy supply in a process called mitochondrial biogenesis(Fig.2a).One of the pathways activated following TCR engagement is the phospho-inositide 3-kinase(PI3K)AKTmTOR pathway7
19、.mTOR is a serine/threonine kinase that can be part of two dis-tinct protein complexes(the mTORC1 complex and the mTORC2 complex);these complexes mediate different signalling pathways to enable metabolic reprogramming in Tcells8,9,resulting in a shift from fatty acid oxidation and pyruvate oxidation
20、 towards glycolysis and glut-aminolysis10,11.The biochemical intermediates of these metabolic pathways enable the generation of nucleotides,amino acids and fatty acids12.When Tcells are activated by antigen-presenting cells(APCs),they undergo asymmetric cell division with asymmetric distribution of
21、MYC,a crucial transcription factor for the differentiation of various effector T(Teff)cell subsets(discussed in the next section).MYC is important for driving metabolic reprogramming in Tcells down-stream of mTORC1 and can regulate the expression of enzymes involved in glycolysis and glutaminolysis.
22、The daughter cells with elevated levels of MYC differenti-ate into Teffcells,whereas the remaining daughter cells(with low levels of MYC)differentiate into memory-like Tcells13.Acute deprivation of MYC compromises both glycolysis and glutaminolysis10.Glycolysis is the major metabolic pathway require
23、d for Tcell activation,a process characterized by an abrupt switch from oxidative phosphorylation to glyco-lysis(known as the Warburg effect);however,given that mitochondrial biogenesis increases in Tcells fol-lowing activation,oxidative phosphorylation might also be involved14.Mitochondrial metabol
24、ic pathways are required for Tcell proliferation to generate ATP for biosynthesis,signalling molecules and reactive oxygen species(ROS)for NFAT activation,a crucial transcrip-tion factor for the production of IL-2(a key death and growth factor for Tcells)15.Tcell differentiation.Different subsets of
25、 Tcells are defined by their TCR composition(for example,chains or chains),the expression of co-receptors(for exam-ple,CD4 for T helper(TH)cells and CD8 for cytotoxic Tcells)and the expression of transcription factors and cytokines16.Metabolic pathways might influence the dif-ferentiation of CD8+Tce
26、lls and THcell subsets.These pathways are flexible and Tcells can adapt to different metabolic requirements.The metabolism of the various Tcell subsets is discussed in more detail inthe follow-ing sections.The metabolic pathways in memory Tcells and regulatory T(Treg)cells are different from those i
27、n Teffcell development and are therefore discussed in a separatesection.Effector Tcell metabolismNaive CD4+Tcells can differentiate into various Teffcell subsets,including TH1,TH17,TH2 and follicular helper T(TFH)cells.Each of the Teffcell subsets utilizes the dif-ferent metabolic pathways downstrea
28、m of the TCR to vary ing extents according to the availability of metab-olites and the function of the Teffcell subset17(Fig.2b).These cells require carbohydrates,proteins and lipids,and limitation of these nutrients diminishes Teffcell responses12.The mTOR signalling pathway is central for controll
29、ingthe development of specific types of Teffcells.For example,mTORC1 activity typically charac-terizes TH1 cell,TH17 cell and CD8+Tcell differentia-tion,whereas combined mTORC1mTORC2 activity is required for TH2cell and TFHcell differentiation8,9.Various immune molecules known to direct the gen-erat
30、ion of distinct Teffcells are thought to be involved in metabolic pathways too.For example,the inducible Tcell co-stimulator(ICOS),a co-stimulatory molecule,activates the mTORC1 and mTORC2 complexes,pro-moting glycolysis,lipogenesis and glucose transporter 1 (GLUT1)-mediated glucose metabolism and s
31、ubse-quent TFHcell responses18.Furthermore,the transcrip-tion factor interferon regulatory factor 4(IRF4)inhibits a transcriptional repressor,BCL6,that blocks glycolytic enzymes19;inhibition of BCL6 promotes glycolysis,a pro-cess thatis essential for TH1 and CD8+Tcell differentiation (as discussed i
32、n the next section)20.Glucose metabolism in effector Tcells.Glycolysis is increased in TH1,TH17 and TFHcells(as well as in CD8+Tcells)compared with quiescent cells10,21,and this path-way is required for the differentiation of Tcells into TH1 and TH17 cell lineages21,22.Transgenic overexpression of G
33、LUT1 in mouse Tcells leads to increased glucose uptake and production of IL-2 and IFN23.By contrast,GLUT1 deficiency in mouse Tcells through deletion of Glut1 decreases the utilization of glucose by CD4+Tcells and results in diminished differentiation to Teffcells and reduced Tcell proliferation24.C
34、onversely,glyco-lysis deprivation supports the development of Tregcells under conditions that induce Tregcell differentiation Key pointsThefateofTcelldifferentiationcanbedeterminedbytheactivityofvariousmetabolicpathwaysinthecell,reflectingthecentralroleofmetabolismincontrollingTcellplasticity.Insyst
35、emiclupuserythematosus(SLE),TcellsarechronicallyactiveasaresultofTcellreceptorrewiring,hypomethylationofgenesrelatedtocellactivation,anincreaseinlipidraftformationandmultifactorialmTORC1activation.ManipulatingmetabolicpathwaysinTcellsisapromisingstrategyinSLEandcouldenabletheinhibitionofpathogenicef
36、fectorTcellactivationanddifferentiationandthepromotionofregulatoryTcells.Nonessential amino acidsSix amino acids that can be synthesized in sufficient quantities in the body(alanine,aspartic acid,asparagine,glutamic acid,serine and selenocysteine),unlike essential amino acids that must be supplied i
37、n the diet.Anabolic metabolism phenotypeA phenotype characterized by rapid biosynthesis of molecules through various metabolic pathways.Mitochondrial biogenesisThe increase in mitochondrial mass within a cell as a result of cellular stress or prolonged activation.This process includes an increase in
38、 metabolic enzymes involved in glycolysis and oxidative phosphorylation and is regulated by AMPK and transcriptional discussed in the next section)21.Although glycolytic activity is high in differentiated TH2 cells21,the impor-tance of glycolysis in TH2 and TFHcell differentiation isunclear.The fate
39、 of Teffcell differentiation is determined by intermediate metabolites involved in the control of glu-cose metabolism,such as hypoxia-inducible factor 1(HIF1)and pyruvate dehydrogenase(PDH).HIF1 regulates glucose metabolism in both CD4+and CD8+Tcells and also controls the differentiation of TH1 and
40、TH17 cells17,18.HIF1 activity is promoted downstream of TCR activation,favouring glycolysis and TH1 and TH17cell differentiation.By contrast,the Ras homologue gene family member A(RhoA),a small GTPase protein,is required for orchestrating glycolysis during TH2 cell differentiation25.mTORC2 regulates
41、 RhoA activity and is thus essential for TH2 cell differentiation8.After the generation of pyruvate(the last step of glyco-lysis),pyruvate can either be converted to lactate in the cytoplasm via lactate dehydrogenase(LDH)or converted into acetyl-CoA in the mitochondria via PDH.The mitochondrial pyru
42、vate carrier(MPC)enables entry of pyruvate into the mitochondria(Fig.3)and specific enzy-mes control the activity of PDH in the mitochondria:pyruvate dehydrogenase phosphatase catalytic subunit 2(PDP2)dephosphorylates PDH,resulting in PDH acti-vation,whereas PDH kinase 1(PDK1)phosphorylates,and henc
43、e inactivates,PDH.The expression of PDP2 itself is suppressed at the transcriptional level by indu-cible cAMP early repressor(ICER)26,an important tran-scriptional factor in TH17 cells.This transcription factor also promotes glutaminolysis(asdiscussed in the next section)by promoting the expression
44、of glutaminase,suppresses the production of IL-2 and promotes the production of IL-17(reF.27).TH17 cells express ICER and increased levels of PDK1(compared with TH1 cells)and thus produce higher lev-els of lactate(and have lower levels of acetyl-CoA)26.Inhibition of PDK1 prevents the formation of TH
45、17 cells2830 and promotes IFN production and TH1 cell dif-ferentiation30.Inhibition of MPC reduces both TH1cell polarization(owing to a reduction in acetyl-CoA pro-duction)and TH17 cell polarization(in the absence of ICER)30,31.Amino acid metabolism in effector Tcells.Amino acids are required in a b
46、road range of cellular processes dur-ing inflammation,including protein synthesis as well as nucleic acid synthesis,the regulation of mTORC1 signalling and the control of stress pathways in Tcells32,33.Glutamine is a non-essential amino acid that is consid-ered the most abundant amino acid in the ci
47、rculation,and its consumption is increased in activated Tcells10.During glutaminolysis,glutamine is hydrolysed to glutamate,GlucoseGlucoseGlutamineMitochondriaPyruvateLactatePentosephosphatepathwayAcetyl-CoAETCGlycolysisFatty acid oxidationTCAcycleOxidativephosphorylationGlutaminolysisNADHFADH2Gluco
48、se-6-phosphateFatty acidFatty acidtransporterGLUT1Amino acidtransporter-ketoglutarateSuccinateCitrateFig.1|metabolic pathways in immune cells.The glucose metabolic pathway consists of both glycolysis,which converts glucose to pyruvate in the cytoplasm,and oxidative phosphorylation,which generates en
49、ergy via the tricarboxylic acid(TCA)cycle in the mitochondria.Pyruvate that enters the mitochondria can be further converted to acetyl coenzyme A(acetyl-CoA)and enter the TCA cycle.Energy can also be generated via metabolism of glutamine (in a process called glutaminolysis)or fatty acids(in a proces
50、s called-oxidation),which both take place in the mitochondria utilizing the TCA cycle machinery.Glucose metabolism under anaerobic conditions converts pyruvate to lactate,diverting glucose metabolism from the TCA cycle.Glucose metabolism under oxygen-sufficient conditions utilizes the machinery in b