TIGIT信号在日本血吸虫感染小鼠Th1/Th2反应平衡中的作用研究
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摘要
目的研究TIGIT信号在日本血吸虫感染过程中Th1/Th2反应平衡中的作用。方法 C57BL/6小鼠感染日本血吸虫尾蚴,并以未感染小鼠作为正常对照。感染0、3、5、8、13周时取小鼠脾脏,采用流式细胞术检测小鼠脾脏淋巴细胞中TIGIT阳性细胞比例,以及TIGIT阴性和TIGIT阳性细胞上Ki67、IFN.γ、IL.4表达水平。结果日本血吸虫感染组小鼠脾脏中TIGIT+细胞占CD4+T细胞的比例显著高于正常对照组(29.30%±0.70%vs.3.09%±0.50%;t=29.09,P<0.01),但感染组和对照组小鼠脾脏中TIGIT+细胞占CD8+T细胞的比例差异无统计学意义(3.61%±0.26%vs.3.58%±0.16%;t=0.108,P>0.05),且感染组和对照组小鼠脾脏中TIGIT+细胞占非T细胞的比例差异亦无统计学意义(1.86%±0.19%vs.1.37%±0.17%;t=1.931,P>0.05)。进一步分析发现,Ki67在TIGIT+细胞上的表达比例(17.03%±0.64%)较其在TIGIT.细胞上表达的比例(6.59%±0.37%)显著升高(t=14.09,P<0.01),而CD4+TIGIT+细胞中Th2/Th1比值显著高于CD4+TIGIT.细胞(39.28%±3.75%vs.11.79%±1.64%;t=6.721,P<0.01)。结论感染日本血吸虫后,CD4+T细胞上TIGIT表达增加,且可能通过诱导Th2细胞增殖进而促进Th2细胞比例增加。
Objective To investigate the role of TIGIT signal in Th1/Th2 balance in the process of Schistosoma japonicum infection.Methods Male C57 BL/6 mice were infected with cercariae of S. japonicum,and normal uninfected mice served as the controls. The percentages of TIGIT+cells,Ki67~+CD3~+CD4~+TIGIT+cells,Ki67~+CD3~+CD4~+TIGIT-cells,IFN-γ+CD3+CD4+TIGIT+cells,IFN-γ+CD3+CD4+TIGIT-cells,IL-4~+CD3~+CD4~+TIGIT+cells and IL-4~+CD3~+CD4~+TIGIT-cells were evaluated in mouse spleen by flow cytometry.Results The proportion of TIGIT~+CD4~+T cells was higher in the spleen of S. japonicum-infected mice than in the normal uninfected mice(29.30%±0.70% vs. 3.09%±0.50%;t = 8.834,P < 0.01). However,no significant difference in the percentages of TIGIT+CD8+T cells between the infection group and normal controls(3.61%±0.26% vs. 3.58%±0.16%;t = 0.108,P > 0.05),and no significant difference was detected in the percentages of TIGIT+cells in non-T cells between the infection group and controls(1.86%±0.19% vs.1.37%±0.17%;t = 1.931,P > 0.05). In addition,the proportion of Ki67 in the TIGIT+cells was higher than that in the TIGIT-cells(17.03%±0.64% vs. 6.59%±0.37%;t = 14.09,P < 0.01). The Th2/Th1 ratio was higher in the TIGIT~+CD4~+T cells than in the TIGIT-CD4~+T cells(39.28%±3.75% vs. 11.79%±1.64%;t =6.721,P < 0.01).Conclusion The TIGIT signaling may be involved in the development of Th2 responses in the mice infected with S. japonicum.
Objective To investigate the role of TIGIT signal in Th1/Th2 balance in the process of Schistosoma japonicum infection.Methods Male C57 BL/6 mice were infected with cercariae of S. japonicum,and normal uninfected mice served as the controls. The percentages of TIGIT+cells,Ki67~+CD3~+CD4~+TIGIT+cells,Ki67~+CD3~+CD4~+TIGIT-cells,IFN-γ+CD3+CD4+TIGIT+cells,IFN-γ+CD3+CD4+TIGIT-cells,IL-4~+CD3~+CD4~+TIGIT+cells and IL-4~+CD3~+CD4~+TIGIT-cells were evaluated in mouse spleen by flow cytometry.Results The proportion of TIGIT~+CD4~+T cells was higher in the spleen of S. japonicum-infected mice than in the normal uninfected mice(29.30%±0.70% vs. 3.09%±0.50%;t = 8.834,P < 0.01). However,no significant difference in the percentages of TIGIT+CD8+T cells between the infection group and normal controls(3.61%±0.26% vs. 3.58%±0.16%;t = 0.108,P > 0.05),and no significant difference was detected in the percentages of TIGIT+cells in non-T cells between the infection group and controls(1.86%±0.19% vs.1.37%±0.17%;t = 1.931,P > 0.05). In addition,the proportion of Ki67 in the TIGIT+cells was higher than that in the TIGIT-cells(17.03%±0.64% vs. 6.59%±0.37%;t = 14.09,P < 0.01). The Th2/Th1 ratio was higher in the TIGIT~+CD4~+T cells than in the TIGIT-CD4~+T cells(39.28%±3.75% vs. 11.79%±1.64%;t =6.721,P < 0.01).Conclusion The TIGIT signaling may be involved in the development of Th2 responses in the mice infected with S. japonicum.
引文
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[11]Inozume T,Yaguchi T,Furuta J,et al.Melanoma cells control antimelanoma CTL responses via interaction between TIGIT and CD155 in the effector phase[J].J Invest Dermatol,2016,136(1):255-263.
[12]Kourepini E,Paschalidis N,Simoes DC,et al.TIGIT enhances antigen-specific Th2 recall responses and allergic disease[J].J Immunol,2016,196(9):3570-3580.
[13]Chan CW,Kay LS,Khadaroo RG,et al.Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties:suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells[J].J Immunol,2003,170(8):4036-4044.
[14]Jihyun Y,Hyunyong L,Youngwoo C,et al.DW2008S and its major constituents from Justicia procumbens exert anti-asthmatic effect via multitargeting activity[J].J Cell Mol Med,2018,in press.
[15]Youm J,Lee H,Chang HB,et al.Justicia procumbens extract(DW2008)selectively suppresses Th2 cytokines in splenocytes and ameliorates ovalbumin-induced airway inflammation in a mouse model of asthma[J].Biol Pharm Bull,2017,40(9):1416-1422.
[16]Zhu L,Kong Y,Zhang J,et al.Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia[J].J Hematol Oncol,2017,10(1):124.
[17]Yang IV,Pedersen BS,Liu A,et al.DNA methylation and childhood asthma in the inner city[J].J Allergy Clin Immunol,2015,136(1):69-80.
[18]Kamran N,Takai Y,Miyoshi J,et al.Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigenpresenting cells[J].PLo S One,2013,8(1):e54406.
[19]Seth S,Maier MK,Qiu Q,et al.The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1[J].Biochem Biophys Res Commun,2007,364(4):959-965.
[20]Bottino C,Castriconi R,Pende D,et al.Identification of PVR(CD155)and Nectin-2(CD112)as cell surface ligands for the human DNAM-1(CD226)activating molecule[J].J Exp Med,2003,198(4):557-567.
[21]Wang J,Vuitton DA,Müller N,et al.Deletion of gibrinogen-like protein 2(FGL-2),a novel CD4+CD25+Treg effector molecule,leads to improved control of Echinococcus multilocularis infection in mice[J].PLo S Negl Trop Dis,2015,9(5):e0003755.
[2]范小琳,高琪,杨俊齐.CD4+T细胞亚群在血吸虫感染中的动态变化及功能研究进展[J].中国血吸虫病防治杂志,2015,27(6):662-668.
[3]Wilson MS,Mentink-Kane MM,Pesce JT,et al.Immunopathology of schistosomiasis[J].Immunol Cell Biol,2007,85(2):148-154.
[4]Chensue SW,Terebuh PD,Warmington KS,et al.Role of IL-4and IFN-gamma in Schistosoma mansoni egg-induced hypersensitivity granuloma formation.Orchestration,relative contribution,and relationship to macrophage function[J].J Immunol,1992,148(3):900-906.
[5]Reiman RM,Thompson RW,Feng CG,et al.Interleukin-5(IL-5)augments the progression of liver fibrosis by regulating IL-13 activity[J].Infect Immun,2006,74(3):1471-1479.
[6]Chuah C,Jones MK,Burke ML,et al.Cellular and chemokinemediated regulation in schistosome-induced hepatic pathology[J].Trends Parasitol,2014,30(3):141-150.
[7]Yu X,Harden K,Gonzalez LC,et al.The surface protein TIGITsuppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells[J].Nat Immunol,2009,10(1):48-57.
[8]Boles KS,Vermi W,Facchetti F,et al.A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC[J].Eur J Immunol,2009,39(3):695-703.
[9]Zhang T,Wang J,Zhou X,et al.Increased expression of TIGITon CD4+T cells ameliorates immune-mediated bone marrow failure of aplastic anemia[J].J Cell Biochem,2014,115(11):1918-1927.
[10]Chew GM,Fujita T,Webb GM,et al.TIGIT marks exhausted Tcells,correlates with disease progression,and serves as a target for immune restoration in HIV and SIV infection[J].PLo S Pathog,2016,12(1):e1005349.
[11]Inozume T,Yaguchi T,Furuta J,et al.Melanoma cells control antimelanoma CTL responses via interaction between TIGIT and CD155 in the effector phase[J].J Invest Dermatol,2016,136(1):255-263.
[12]Kourepini E,Paschalidis N,Simoes DC,et al.TIGIT enhances antigen-specific Th2 recall responses and allergic disease[J].J Immunol,2016,196(9):3570-3580.
[13]Chan CW,Kay LS,Khadaroo RG,et al.Soluble fibrinogen-like protein 2/fibroleukin exhibits immunosuppressive properties:suppressing T cell proliferation and inhibiting maturation of bone marrow-derived dendritic cells[J].J Immunol,2003,170(8):4036-4044.
[14]Jihyun Y,Hyunyong L,Youngwoo C,et al.DW2008S and its major constituents from Justicia procumbens exert anti-asthmatic effect via multitargeting activity[J].J Cell Mol Med,2018,in press.
[15]Youm J,Lee H,Chang HB,et al.Justicia procumbens extract(DW2008)selectively suppresses Th2 cytokines in splenocytes and ameliorates ovalbumin-induced airway inflammation in a mouse model of asthma[J].Biol Pharm Bull,2017,40(9):1416-1422.
[16]Zhu L,Kong Y,Zhang J,et al.Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia[J].J Hematol Oncol,2017,10(1):124.
[17]Yang IV,Pedersen BS,Liu A,et al.DNA methylation and childhood asthma in the inner city[J].J Allergy Clin Immunol,2015,136(1):69-80.
[18]Kamran N,Takai Y,Miyoshi J,et al.Toll-like receptor ligands induce expression of the costimulatory molecule CD155 on antigenpresenting cells[J].PLo S One,2013,8(1):e54406.
[19]Seth S,Maier MK,Qiu Q,et al.The murine pan T cell marker CD96 is an adhesion receptor for CD155 and nectin-1[J].Biochem Biophys Res Commun,2007,364(4):959-965.
[20]Bottino C,Castriconi R,Pende D,et al.Identification of PVR(CD155)and Nectin-2(CD112)as cell surface ligands for the human DNAM-1(CD226)activating molecule[J].J Exp Med,2003,198(4):557-567.
[21]Wang J,Vuitton DA,Müller N,et al.Deletion of gibrinogen-like protein 2(FGL-2),a novel CD4+CD25+Treg effector molecule,leads to improved control of Echinococcus multilocularis infection in mice[J].PLo S Negl Trop Dis,2015,9(5):e0003755.