日本血吸虫感染过程中糖酵解途径对调节性T细胞产生的影响
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摘要
目的探索日本血吸虫感染过程中糖酵解途径对小鼠调节性T(Treg)细胞数量和功能的影响。方法建立日本血吸虫感染小鼠模型,用糖酵解抑制剂2-Deoxy-D-glucose(2DG)或PBS对日本血吸虫感染小鼠进行6次腹腔注射后,分离脾脏细胞和肠系膜淋巴结,采用流式细胞术(FCM)检测分离得到的细胞中Glut1~+CD4~+T细胞以及Treg细胞比例。结果未感染组小鼠脾脏(43.58%±2.50%vs.21.15%±0.96%;t=8.834,P<0.01)和肠系膜淋巴结中Glut1~+CD4~+T细胞比例(38.97%±1.97%vs.28.40%±2.11%;t=3.662,P<0.05)均显著高于感染日本血吸虫8周小鼠,但未感染组小鼠脾脏(6.83%±0.21%vs.13.30%±0.35%;t=15.65,P<0.01)和肠系膜淋巴结中Treg细胞比例(8.26%±0.15%vs.14.37%±0.44%;t=13.14,P<0.01)均显著低于感染组小鼠。感染小鼠给与2DG腹腔注射后,脾脏(15.50%±0.76%vs.13.07%±0.15%;t=3.130,P<0.05)和肠系膜淋巴结中Treg细胞比例(17.00%±0.41%vs.13.83%±0.18%;t=6.947,P<0.01)显著高于给与PBS注射小鼠。结论糖酵解途径抑制了日本血吸虫感染小鼠Treg细胞分化。
Objective To assess the influence of glycolytic pathway on the proportion and numbers of regulatory T cells during Schistosoma japonicum infection.Methods A S. japonicum-infected mouse model was established,and C57/BL6 male mice infected with S. japonicum were subjected to intraperitoneal injections of with the glycolytic inhibitor 2-Deoxy-D-glucose(2 DG)or PBS for 6 times,and then the cells from spleen or mesenteric lymph nodes(LNs)were isolated and analyzed by flow cytometry(FCM)to detect the percentage of Glut1~+CD4~+T cells and Treg cells.Results The proportions of Glut1~+CD4~+T cells in the spleen(43.58%±2.50% vs. 21.15%±0.96%;t = 8.834,P < 0.01)and mesenteric LNs(38.97%±1.97% vs. 28.40%±2.11%;t = 3.662,P < 0.05)were higher in the normal mice than those in the infected mice,and the percentages of Treg cells in the spleen(6.83%±0.21% vs. 13.30%±0.35%;t = 15.65,P < 0.01)and LNs(8.26%±0.15% vs. 14.37%±0.44%;t =13.14,P < 0.01)were lower in the normal mice than those in the infected mice. In addition,the proportions of Treg cells in the spleen(15.50%±0.76% vs. 13.07%±0.15%;t = 3.130,P < 0.05)and LNs(17.00% ± 0.41% vs. 13.83% ± 0.18%;t = 6.947,P < 0.01)were higher in the infected mice injected intraperitoneally with 2 DG than those in the infected mice injected intraperitoneally with PBS.Conclusion Glycolytic pathway inhibits Treg differentiation in the spleen and mesenteric LNs of S. japonicum-infected mice.
Objective To assess the influence of glycolytic pathway on the proportion and numbers of regulatory T cells during Schistosoma japonicum infection.Methods A S. japonicum-infected mouse model was established,and C57/BL6 male mice infected with S. japonicum were subjected to intraperitoneal injections of with the glycolytic inhibitor 2-Deoxy-D-glucose(2 DG)or PBS for 6 times,and then the cells from spleen or mesenteric lymph nodes(LNs)were isolated and analyzed by flow cytometry(FCM)to detect the percentage of Glut1~+CD4~+T cells and Treg cells.Results The proportions of Glut1~+CD4~+T cells in the spleen(43.58%±2.50% vs. 21.15%±0.96%;t = 8.834,P < 0.01)and mesenteric LNs(38.97%±1.97% vs. 28.40%±2.11%;t = 3.662,P < 0.05)were higher in the normal mice than those in the infected mice,and the percentages of Treg cells in the spleen(6.83%±0.21% vs. 13.30%±0.35%;t = 15.65,P < 0.01)and LNs(8.26%±0.15% vs. 14.37%±0.44%;t =13.14,P < 0.01)were lower in the normal mice than those in the infected mice. In addition,the proportions of Treg cells in the spleen(15.50%±0.76% vs. 13.07%±0.15%;t = 3.130,P < 0.05)and LNs(17.00% ± 0.41% vs. 13.83% ± 0.18%;t = 6.947,P < 0.01)were higher in the infected mice injected intraperitoneally with 2 DG than those in the infected mice injected intraperitoneally with PBS.Conclusion Glycolytic pathway inhibits Treg differentiation in the spleen and mesenteric LNs of S. japonicum-infected mice.
引文
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[15]Wen X,Lei H,Ying C,et al.Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice[J].PLo SNegl Trop Dis,2011,5(11):e1399.
[16]Wang B,Liang S,Wang Y,et al.Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSLKO mice[J].PLo S Negl Trop Dis,2015,9(1):e0003434.
[17]Chen X,Yang X,Li Y,et al.Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection[J].PLo S Pathog,2014,10(5):e1004097.
[18]Chen X,Li W,Zhang Y,et al.Distribution of peripheral memory T follicular helper cells in patients with schistosomiasis japonica[J].PLo S Negl Trop Dis,2015,9(8):e0004015.
[19]Tang Q,Bluestone JA.The Foxp3+regulatory T cell:a jack of all trades,master of regulation[J].Nat Immunol,2008,9(3):239-244.
[20]Tadokoro CE,Guy S,Shen S,et al.Regulatory T cells inhibit stable contacts between CD4+T cells and dendritic cells in vivo[J].JExp Med,2006,203(3):505-511.
[21]Sojka DK,Huang YH,Fowell DJ.Mechanisms of regulatory T-cell suppression-a diverse arsenal for a moving target[J].Immunology,2008,124(1):13-22.
[22]Michalek RD,Gerriets VA,Jacobs SR,et al.Cutting edge:distinct glycolytic and lpid oxidative metabolic programs are essential for effector and regulatory CD4+T cell subsets[J].J Immunol,2011,186(6):3299-3303.
[23]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].Nature Commun,2017,8:15677.
[24]Fassett MS,Jiang W,D′Alise AM,et al.Nuclear receptor Nr4a1modulates both regulatory T-cell(Treg)differentiation and clonal deletion[J].Proc Natl Acad Sci U S A,2012,109(10):3891-3896.
[2]张利娟,徐志敏,钱颖骏,等.2016年全国血吸虫病疫情通报[J].中国血吸虫病防治杂志,2017,29(6):669-677.
[3]Pearce EJ,Macdonald AS.The immunobiology of schistosomiasis[J].Nat Rev Immunol,2002,2(7):499-511.
[4]Togashi Y,Nishikawa H.Regulatory T cells:molecular and cellular basis for immunoregulation[J].Curr Top Microbiol Immunol,2017,410:3-27.
[5]von Boehmer H,Daniel C.Therapeutic opportunities for manipulating T(Reg)cells in autoimmunity and cancer[J].Nat Rev Drug Discov,2013,12(1):51-63.
[6]Qiao M,Thornton AM,Shevach EM.CD4+CD25+,regulatory Tcells render naive CD4+CD25-T cells anergic and suppressive[J].Immunology,2007,120(4):447-455.
[7]Cederbom L,Hall H,Ivars F.CD4+CD25+regulatory T cells downregulate co-stimulatory molecules on antigen-presenting cells[J].Eur J Immunol,2000,30(6):1538-1543.
[8]Singh KP,Gerard HC,Hudson AP,et al.Retroviral Foxp3 gene transfer ameliorates liver granuloma pathology in Schistosoma mansoni infected mice[J].Immunology,2005,114(3):410-417.
[9]Zhang W,Zhu J,Song X,et al.An association of Aquaporin-4with the immunoregulation of liver pathology in mice infected with Schistosoma japonicum[J].Parasit Vectors,2015,8(1):37.
[10]Shanmugam M,Mcbrayer SK,Rosen ST.Targeting the Warburg effect in hematological malignancies:from PET to therapy[J].Curr Opin Oncol,2009,21(6):531-536.
[11]Macintyre AN,Gerriets VA,Nichols AG,et al.The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function[J].Cell Metab,2014,20(1):61-72.
[12]Shi LZ,Wang R,Huang G,et al.HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells[J].J Exp Med,2011,208(7):1367-1376.
[13]黄一心.吡喹酮抗血吸虫作用机理的奥秘[J].中国血吸虫病防治杂志,2010,22(2):101-104.
[14]Zhou S,Jin X,Li Y,et al.Blockade of PD-1 signaling enhances Th2 cell responses and aggravates liver immunopathology in mice with schistosomiasis japonica[J].PLo S Negl Trop Dis,2016,10(10):e0005094.
[15]Wen X,Lei H,Ying C,et al.Dynamics of Th17 cells and their role in Schistosoma japonicum infection in C57BL/6 mice[J].PLo SNegl Trop Dis,2011,5(11):e1399.
[16]Wang B,Liang S,Wang Y,et al.Th17 down-regulation is involved in reduced progression of schistosomiasis fibrosis in ICOSLKO mice[J].PLo S Negl Trop Dis,2015,9(1):e0003434.
[17]Chen X,Yang X,Li Y,et al.Follicular helper T cells promote liver pathology in mice during Schistosoma japonicum infection[J].PLo S Pathog,2014,10(5):e1004097.
[18]Chen X,Li W,Zhang Y,et al.Distribution of peripheral memory T follicular helper cells in patients with schistosomiasis japonica[J].PLo S Negl Trop Dis,2015,9(8):e0004015.
[19]Tang Q,Bluestone JA.The Foxp3+regulatory T cell:a jack of all trades,master of regulation[J].Nat Immunol,2008,9(3):239-244.
[20]Tadokoro CE,Guy S,Shen S,et al.Regulatory T cells inhibit stable contacts between CD4+T cells and dendritic cells in vivo[J].JExp Med,2006,203(3):505-511.
[21]Sojka DK,Huang YH,Fowell DJ.Mechanisms of regulatory T-cell suppression-a diverse arsenal for a moving target[J].Immunology,2008,124(1):13-22.
[22]Michalek RD,Gerriets VA,Jacobs SR,et al.Cutting edge:distinct glycolytic and lpid oxidative metabolic programs are essential for effector and regulatory CD4+T cell subsets[J].J Immunol,2011,186(6):3299-3303.
[23]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].Nature Commun,2017,8:15677.
[24]Fassett MS,Jiang W,D′Alise AM,et al.Nuclear receptor Nr4a1modulates both regulatory T-cell(Treg)differentiation and clonal deletion[J].Proc Natl Acad Sci U S A,2012,109(10):3891-3896.