Treg/Th17代谢特点及相关通路对Treg/Th17平衡的影响
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摘要
调节性T细胞(Treg)与辅助性T细胞Th17(Th17)的动态平衡是维持免疫稳定的重要机制,与炎症、肿瘤及自身免疫疾病密切相关,近些年,越来越多的研究表明Treg与Th17具有不同的代谢方式,mTOR信号通路、AMPK信号通路及一些小分子蛋白可通过调节细胞代谢影响Treg/Th17平衡。本文作者查阅近年文献,就细胞代谢及其调控机制与Treg/Th17平衡的相互关系作一综述。
The balance between T regulatory cell( Treg) and T helper 17 cells( Th17) is closely related to the progression of inflammatory diseases,tumor and autoimmune diseases. Recent studies have demonstrated a different metabolic features in Treg and Th17. m TOR,AMPK signal pathway and some molecule protein could regulate Treg/Th17 balance through modulating cell metabolic process. The author search for the literatures and make a review about metabolic process and relative pathways in regulating Treg/Th17 balance.
The balance between T regulatory cell( Treg) and T helper 17 cells( Th17) is closely related to the progression of inflammatory diseases,tumor and autoimmune diseases. Recent studies have demonstrated a different metabolic features in Treg and Th17. m TOR,AMPK signal pathway and some molecule protein could regulate Treg/Th17 balance through modulating cell metabolic process. The author search for the literatures and make a review about metabolic process and relative pathways in regulating Treg/Th17 balance.
引文
[1]晁康,张盛洪,陈旻湖,等.CD4+T细胞与炎症性肠病[J].胃肠病学和肝病学杂志,2010,19(11):1058-1061.Chao K,Zhang SH,Chen MH,et al.CD4+T cell and inflammatory bowel disease[J].Chin J Gastroenterol Hepatol,2010,19(11):1058-1061.
[2]吴小丽,张婷,王昕婧,等.肿瘤相关巨噬细胞通过分泌IL-10影响上皮性卵巢癌肿瘤微环境中T细胞亚群Treg/Th17失衡[J].中国免疫学杂志,2014,30(12):1585-1590.Wu XL,Zhang T,Wang XQ,et al.Impact of tumor-associate macrophages(TAM)to imbalance of Treg/Th17 in Eoc microenvironment[J].Chin J Immunol,2014(12):1585-1590.
[3]Gharibi B,Ghuman M,Hughes FJ.DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1αand m TOR signalling[J].Sci Rep,2016,6:36889.
[4]Wawman RE,Bartlett H,Oo YH.Regulatory T cell metabolism in the hepatic microenvironment[J].Front Immunol,2017,8:1889.
[5]Gerriets VA,Kishton RJ,Nichols AG,et al.Metabolic programming and PDHK1 control CD4+T cell subsets and inflammation[J].JClin Investig,2015,125(1):194-207.
[6]Lewis Z,Shi RN,Wang GH,et al.HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells[J].J Exp Med,2011,208(7):1367-1376.
[7]Basu S,Hubbard B,Shevach EM.Foxp3-mediated inhibition of Akt inhibits Glut1(glucose transporter 1)expression in human T regulatory cells[J].J Leukoc Biol,2015,97(2):279-283.
[8]Cloer C.m TORC1 couples immune signals and metabolic programming to establish T(reg)-cell function.[J].Nature,2013,499(7459):485-490.
[9]Michalek RD,Gerriets VA,Jacobs SR,et al.Cutting edge:distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+T cell subsets[J].J Immunol,2011,186(6):3299.
[10]Kishore M,Kcp C,Fu H,et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis[J].Immunity,2017,47(5):875-889.e10.
[11]Berod L,Friedrich C,Nandan A,et al.Erratum:De novo fatty acid synthesis controls the fate between regulatory T and T helper17 cells[J].Nat Med,2014,20(11):1327-1333.
[12]Roger Geiger,Jan C.Rieckmann,Tobias Wolf,et al.L-Arginine modulates T cell metabolism and enhances survival and antitumor activity[J].Cell,2016,167(3):829-842.e13.
[13]Resheq YJ,Li KK,Ward ST,et al.Contact-dependent depletion of hydrogen peroxide by catalase is a novel mechanism of myeloid-derived suppressor cell induction operating in human hepatic stellate cells[J].J Immunol,2015,194(6):2578-2586.
[14]Sinclair LV,Rolf J,Emslie E,et al.Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation[J].Nat Immunol,2013,14(5):500.
[15]Klysz D,Tai X,Robert PA,et al.Glutamine-dependentα-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation[J].Sci Signal,2015,8(396):ra97.
[16]Chapman NM,Chi H.m TOR links environmental signals to T cell fate decisions[J].Front Immunol,2015,5(686):686.
[17]Veldhoen M,Hirota K,Westendorf AM,et al.The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins[J].Nature,2008,453(7191):106-109.
[18]Veldhoen MH,Hirota K,Christensen J,et al.Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells[J].J Exp Med,2009,206(1):43-49.
[19]Guertin DA,Sabatini DM.Defining the Role of m TOR in Cancer[J].Cancer Cell,2007,12(1):9-22.
[20]Kane LP,Weiss A.The PI-3 kinase/Akt pathway and T cell activation:pleiotropic pathways downstream of PIP3[J].Immunological Rev,2003,192(1):7-20.
[21]Wieman HL,Wofford JA,Rathmell JC.Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking[J].Mol Biol Cell,2007,18(4):1437-1446.
[22]Cybulski N,Hall MN.TOR complex 2:a signaling pathway of its own[J].Trends Biochem Sci,2009,34(12):620-627.
[23]Guertin DA,Stevens DM,Thoreen CC,et al.Ablation in mice of the m TORC components raptor,rictor,or m LST8,Revealsthat m TORC2 is required for signaling to Akt-FOXO and PKCα,but not S6K1[J].Developmental Cell,2006,11(6):859-871.
[24]Sarbassov DD,Guertin DA,Ali SM,et al.Phosphorylation and Regulation of Akt/PKB by the Rictor-m TOR Complex[J].Science,2005,307(5712):1098.
[25]Delgoffe GM,Kole TP,Zheng Y,et al.The m TOR Kinase Differentially Regulates Effector and Regulatory T Cell Lineage Commitment[J].Immunity,2009,30(6):832-844.
[26]Sokol H,Diane M,Christophe B.The AKT-m TOR axis regulates de novo differentiation of CD4+Foxp3+cells[J].J Exp Med,2008,205(3):565-574.
[27]Sauer S,Bruno L,Hertweck A,et al.T cell receptor signaling controls Foxp3 expression via PI3K,Akt,and m TOR[J].Proc Natl Acad Sci U S A,2008,105(22):7797-7802.
[28]Liu G,Burns S,Huang G,et al.S1P1 receptor overrides regulatory T cell-mediated immune suppression through Akt-m TOR[J].Nat Immunol,2009,10(7):769-777.
[29]Liu G,Yang K,Burns S,et al.S1P1-m TOR axis directs the reciprocal differentiation of TH1 and regulatory T cells[J].Nat Immunol,2010,11(11):1047-1056.
[30]Gomezrodriguez J,Wohlfert EA,Handon R,et al.Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells[J].J Exp Med,2014,211(3):529.
[31]Shrestha S,Yang K,Guy C,et al.Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses[J].Nat Immunol,2015,16(2):178.
[32]Huynh A,Dupage M,Priyadharshini B,et al.The phosphatase PTEN-mediated control of PI-3 kinase in Tregs cells maintains homeostasis and lineage stability[J].Nat Immunol,2015,16(2):188-196.
[33]Barbi J,Pardoll D,Pan F.Metabolic control of the Treg/Th17 axis[J].Immunological Rev,2013,252(1):52-77.
[34]Waickman AT,Powell JD.m TOR,metabolism,and the regulation of T-cell differentiation and function[J].Immunological Rev,2012,249(1):43-58.
[35]Delgoffe GM,Pollizzi KN,Waickman AT,et al.The kinase m TORregulates the differentiation of helper T cells through the selective activation of signaling by m TORC1 and m TORC2[J].Nat Immunol,2011,12(4):295-303.
[36]Ai I,Nagai S,Goda N,et al.Dynamic regulation of Th17 differentiation by oxygen concentrations[J].Int Immunol,2012,24(3):137-146.
[37]Zhang F,Liu G,Li D,et al.DDIT4 and Associated lnc DDIT4Modulate Th17 Differentiation through the DDIT4/TSC/m TORPathway[J].J Immunol,2018,200(5):ji1601689.
[38]Hardie DG.AMP-activated/SNF1 protein kinases:conserved guardians of cellular energy[J].Nat Rev Mol Cell Biol,2007,8(10):774-785.
[39]Ma EH,Poffenberger MC,Wong HT,et al.The role of AMPK in Tcell metabolism and function[J].Curr Opin Immunol,2017,46:45-52.
[40]Peter T,Hawley SA,Clarke RG,et al.Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+in T lymphocytes[J].J Exp Med,2006,203(7):1665-1670.
[41]Gualdoni GA,Mayer KA,GSchl L,et al.The AMP analog AICARmodulates the Treg/Th17 axis through enhancement of fatty acid oxidation[J].Faseb J,2016,30(11):3800-3809.
[42]Park MJ,Lee SY,Moon SJ,et al.Metformin attenuates GVHD via restricting m TOR/STAT3 and promoting AMPK-Autophagy for the balance between Th17 and Tregs[J].Translational Res,2016,173:115-130.
[43]He N,Fan W,Henriquez B,et al.Metabolic control of regulatory T cell(Treg)survival and function by Lkb1[J].Proc Natl Acad Sci U S A,2017,114(47):12542-12547.
[44]Yang K,Blanco DB,Neale G,et al.Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling[J].Nature,2017,548(7669):602-606.
[45]Angelin A,Gil-De-G2Mez L,Dahiya S,et al.Foxp3 Reprograms TCell Metabolism to Function in Low-Glucose,High-Lactate Environments[J].Cell Metabolism,2017,25(6):1282-1293.
[46]Mckarns S.Selective deletion of estrogen receptor alpha in Fox P3+CD4+T cells influences peripheral T cell homeostasis(BA11P.139)[J].J Immunol,2015,194(1):21.
[47]Michalek RD,Gerriets VA,Nichols AG,et al.Estrogen-related receptor-αis a metabolic regulator of effector T-cell activation and differentiation[J].Proc Natl Acad Sci U S A,2011,108(45):18348-18353.
[48]Joseph SB,Castrillo A,Laffitte BA,et al.Reciprocal regulation of inflammation and lipid metabolism by liver X receptors[J].Nat Med,2003,9(2):213-219.
[49]Cui GL,Qin X,Wu LL,et al.Liver X receptor(LXR)mediates negative regulation of mouse and human Th17 differentiation.[J].J Clin Investi,2011,121(2):658-670.
[50]Vucic E,Calcagno C,Dickson SD,et al.Regression of inflammation in atherosclerosis by the LXR agonist R211945:a noninvasive assessment and comparison with atorvastatin[J].Jacc Cardiovasc Imaging,2012,5(8):819-828.
[51]Kato H,Perl A.The IL-21-m TOR axis blocks treg differentiation and function by suppression of autophagy in patients with systemic lupus erythematosus[J].Arthritis Rheumatol,2017,70(3):427-438.
[52]Zhang J,Shan J,Chen X,et al.Celastrol mediates Th17 and Treg cell generation via metabolic signaling[J].Biochem Biophysical Res Commun,2018,497(3):883-889.
[53]Layman AAK,Deng G,O'Leary CE,et al.Ndfip1 restricts m TORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease[J].Nat Commun,2017,8:15677.
[2]吴小丽,张婷,王昕婧,等.肿瘤相关巨噬细胞通过分泌IL-10影响上皮性卵巢癌肿瘤微环境中T细胞亚群Treg/Th17失衡[J].中国免疫学杂志,2014,30(12):1585-1590.Wu XL,Zhang T,Wang XQ,et al.Impact of tumor-associate macrophages(TAM)to imbalance of Treg/Th17 in Eoc microenvironment[J].Chin J Immunol,2014(12):1585-1590.
[3]Gharibi B,Ghuman M,Hughes FJ.DDIT4 regulates mesenchymal stem cell fate by mediating between HIF1αand m TOR signalling[J].Sci Rep,2016,6:36889.
[4]Wawman RE,Bartlett H,Oo YH.Regulatory T cell metabolism in the hepatic microenvironment[J].Front Immunol,2017,8:1889.
[5]Gerriets VA,Kishton RJ,Nichols AG,et al.Metabolic programming and PDHK1 control CD4+T cell subsets and inflammation[J].JClin Investig,2015,125(1):194-207.
[6]Lewis Z,Shi RN,Wang GH,et al.HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells[J].J Exp Med,2011,208(7):1367-1376.
[7]Basu S,Hubbard B,Shevach EM.Foxp3-mediated inhibition of Akt inhibits Glut1(glucose transporter 1)expression in human T regulatory cells[J].J Leukoc Biol,2015,97(2):279-283.
[8]Cloer C.m TORC1 couples immune signals and metabolic programming to establish T(reg)-cell function.[J].Nature,2013,499(7459):485-490.
[9]Michalek RD,Gerriets VA,Jacobs SR,et al.Cutting edge:distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+T cell subsets[J].J Immunol,2011,186(6):3299.
[10]Kishore M,Kcp C,Fu H,et al.Regulatory T cell migration is dependent on glucokinase-mediated glycolysis[J].Immunity,2017,47(5):875-889.e10.
[11]Berod L,Friedrich C,Nandan A,et al.Erratum:De novo fatty acid synthesis controls the fate between regulatory T and T helper17 cells[J].Nat Med,2014,20(11):1327-1333.
[12]Roger Geiger,Jan C.Rieckmann,Tobias Wolf,et al.L-Arginine modulates T cell metabolism and enhances survival and antitumor activity[J].Cell,2016,167(3):829-842.e13.
[13]Resheq YJ,Li KK,Ward ST,et al.Contact-dependent depletion of hydrogen peroxide by catalase is a novel mechanism of myeloid-derived suppressor cell induction operating in human hepatic stellate cells[J].J Immunol,2015,194(6):2578-2586.
[14]Sinclair LV,Rolf J,Emslie E,et al.Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation[J].Nat Immunol,2013,14(5):500.
[15]Klysz D,Tai X,Robert PA,et al.Glutamine-dependentα-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation[J].Sci Signal,2015,8(396):ra97.
[16]Chapman NM,Chi H.m TOR links environmental signals to T cell fate decisions[J].Front Immunol,2015,5(686):686.
[17]Veldhoen M,Hirota K,Westendorf AM,et al.The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins[J].Nature,2008,453(7191):106-109.
[18]Veldhoen MH,Hirota K,Christensen J,et al.Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells[J].J Exp Med,2009,206(1):43-49.
[19]Guertin DA,Sabatini DM.Defining the Role of m TOR in Cancer[J].Cancer Cell,2007,12(1):9-22.
[20]Kane LP,Weiss A.The PI-3 kinase/Akt pathway and T cell activation:pleiotropic pathways downstream of PIP3[J].Immunological Rev,2003,192(1):7-20.
[21]Wieman HL,Wofford JA,Rathmell JC.Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking[J].Mol Biol Cell,2007,18(4):1437-1446.
[22]Cybulski N,Hall MN.TOR complex 2:a signaling pathway of its own[J].Trends Biochem Sci,2009,34(12):620-627.
[23]Guertin DA,Stevens DM,Thoreen CC,et al.Ablation in mice of the m TORC components raptor,rictor,or m LST8,Revealsthat m TORC2 is required for signaling to Akt-FOXO and PKCα,but not S6K1[J].Developmental Cell,2006,11(6):859-871.
[24]Sarbassov DD,Guertin DA,Ali SM,et al.Phosphorylation and Regulation of Akt/PKB by the Rictor-m TOR Complex[J].Science,2005,307(5712):1098.
[25]Delgoffe GM,Kole TP,Zheng Y,et al.The m TOR Kinase Differentially Regulates Effector and Regulatory T Cell Lineage Commitment[J].Immunity,2009,30(6):832-844.
[26]Sokol H,Diane M,Christophe B.The AKT-m TOR axis regulates de novo differentiation of CD4+Foxp3+cells[J].J Exp Med,2008,205(3):565-574.
[27]Sauer S,Bruno L,Hertweck A,et al.T cell receptor signaling controls Foxp3 expression via PI3K,Akt,and m TOR[J].Proc Natl Acad Sci U S A,2008,105(22):7797-7802.
[28]Liu G,Burns S,Huang G,et al.S1P1 receptor overrides regulatory T cell-mediated immune suppression through Akt-m TOR[J].Nat Immunol,2009,10(7):769-777.
[29]Liu G,Yang K,Burns S,et al.S1P1-m TOR axis directs the reciprocal differentiation of TH1 and regulatory T cells[J].Nat Immunol,2010,11(11):1047-1056.
[30]Gomezrodriguez J,Wohlfert EA,Handon R,et al.Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells[J].J Exp Med,2014,211(3):529.
[31]Shrestha S,Yang K,Guy C,et al.Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses[J].Nat Immunol,2015,16(2):178.
[32]Huynh A,Dupage M,Priyadharshini B,et al.The phosphatase PTEN-mediated control of PI-3 kinase in Tregs cells maintains homeostasis and lineage stability[J].Nat Immunol,2015,16(2):188-196.
[33]Barbi J,Pardoll D,Pan F.Metabolic control of the Treg/Th17 axis[J].Immunological Rev,2013,252(1):52-77.
[34]Waickman AT,Powell JD.m TOR,metabolism,and the regulation of T-cell differentiation and function[J].Immunological Rev,2012,249(1):43-58.
[35]Delgoffe GM,Pollizzi KN,Waickman AT,et al.The kinase m TORregulates the differentiation of helper T cells through the selective activation of signaling by m TORC1 and m TORC2[J].Nat Immunol,2011,12(4):295-303.
[36]Ai I,Nagai S,Goda N,et al.Dynamic regulation of Th17 differentiation by oxygen concentrations[J].Int Immunol,2012,24(3):137-146.
[37]Zhang F,Liu G,Li D,et al.DDIT4 and Associated lnc DDIT4Modulate Th17 Differentiation through the DDIT4/TSC/m TORPathway[J].J Immunol,2018,200(5):ji1601689.
[38]Hardie DG.AMP-activated/SNF1 protein kinases:conserved guardians of cellular energy[J].Nat Rev Mol Cell Biol,2007,8(10):774-785.
[39]Ma EH,Poffenberger MC,Wong HT,et al.The role of AMPK in Tcell metabolism and function[J].Curr Opin Immunol,2017,46:45-52.
[40]Peter T,Hawley SA,Clarke RG,et al.Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+in T lymphocytes[J].J Exp Med,2006,203(7):1665-1670.
[41]Gualdoni GA,Mayer KA,GSchl L,et al.The AMP analog AICARmodulates the Treg/Th17 axis through enhancement of fatty acid oxidation[J].Faseb J,2016,30(11):3800-3809.
[42]Park MJ,Lee SY,Moon SJ,et al.Metformin attenuates GVHD via restricting m TOR/STAT3 and promoting AMPK-Autophagy for the balance between Th17 and Tregs[J].Translational Res,2016,173:115-130.
[43]He N,Fan W,Henriquez B,et al.Metabolic control of regulatory T cell(Treg)survival and function by Lkb1[J].Proc Natl Acad Sci U S A,2017,114(47):12542-12547.
[44]Yang K,Blanco DB,Neale G,et al.Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling[J].Nature,2017,548(7669):602-606.
[45]Angelin A,Gil-De-G2Mez L,Dahiya S,et al.Foxp3 Reprograms TCell Metabolism to Function in Low-Glucose,High-Lactate Environments[J].Cell Metabolism,2017,25(6):1282-1293.
[46]Mckarns S.Selective deletion of estrogen receptor alpha in Fox P3+CD4+T cells influences peripheral T cell homeostasis(BA11P.139)[J].J Immunol,2015,194(1):21.
[47]Michalek RD,Gerriets VA,Nichols AG,et al.Estrogen-related receptor-αis a metabolic regulator of effector T-cell activation and differentiation[J].Proc Natl Acad Sci U S A,2011,108(45):18348-18353.
[48]Joseph SB,Castrillo A,Laffitte BA,et al.Reciprocal regulation of inflammation and lipid metabolism by liver X receptors[J].Nat Med,2003,9(2):213-219.
[49]Cui GL,Qin X,Wu LL,et al.Liver X receptor(LXR)mediates negative regulation of mouse and human Th17 differentiation.[J].J Clin Investi,2011,121(2):658-670.
[50]Vucic E,Calcagno C,Dickson SD,et al.Regression of inflammation in atherosclerosis by the LXR agonist R211945:a noninvasive assessment and comparison with atorvastatin[J].Jacc Cardiovasc Imaging,2012,5(8):819-828.
[51]Kato H,Perl A.The IL-21-m TOR axis blocks treg differentiation and function by suppression of autophagy in patients with systemic lupus erythematosus[J].Arthritis Rheumatol,2017,70(3):427-438.
[52]Zhang J,Shan J,Chen X,et al.Celastrol mediates Th17 and Treg cell generation via metabolic signaling[J].Biochem Biophysical Res Commun,2018,497(3):883-889.
[53]Layman AAK,Deng G,O'Leary CE,et al.Ndfip1 restricts m TORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease[J].Nat Commun,2017,8:15677.