β-catenin调控免疫细胞生存和分化及其机制研究
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摘要
第一部分Fibronectin通过β-catenin途径维持NK细胞的生存
组织微环境和细胞外基质分子在维持细胞生存促进细胞分化过程中具有重要作用。NK细胞是一类短寿命的细胞类型，尤其小鼠NK细胞分离后在体外存活时间更是少于24小时，因此需要在体外培养体系中加入外源性的细胞因子如IL-12、IL-15以维持小鼠NK细胞的生存。但是很多研究认为NK细胞的体内存活时间远远大于体外，表明体内不同组织微环境为NK细胞的生存提供了支持环境。但是细胞外基质分子如Fibronectin是否以及如何支持NK细胞的生存仍不为人所知。在本课题中，我们发现适当浓度的Fibronectin(10μg／ml)能在体外维持NK细胞的生存。
在探讨Fibronectin维持NK细胞生存的信号机制中，我们发现Fibronectin作用NK细胞后能够上调抗凋亡分子Bcl-2的表达。进一步研究发现，Fibronectin通过结合NK细胞表面的CD11b受体，募集并活化信号分子Src，Src作为β-catenin的上游信号分子，通过与β-catenin直接相互作用，导致β-catenin活化、入核。β-catenin的活化激活Erk分子，进而上调抗凋亡分子Bcl-2的表达，促进NK细胞的存活。同时，Fibronectin并不能维持CD11b阴性的NK细胞以及β-catenin缺陷的NK细胞的体外存活。因此，我们发现Fibronectin通过CD11b／Src／β-catenin途径活化ERK上调Bcl-2的表达从而维持NK细胞的生存。
第二部分TLR4和TLR9配体诱导的调节性单核细胞通过膜结
合型TGF-β和β-catenin通路诱导调节性T细胞的研究
调节性T细胞(Regulatory T cells，Treg)在抑制机体免疫反应和阻止有害的自身免疫应答中具有重要的作用。在免疫应答后期，Treg可以削弱效应性T细胞的功能，将免疫应答控制在一定限度内。许多流行病学研究以及实验研究提示一些Toll样受体(TLR)激动剂在自身免疫性疾病和哮喘的发病中具有保护作用。宿主持续性暴露于低剂量TLR激动剂后有助于维持体内一定数量的CD4~+FoxP3~+调节性T细胞，从而维持了机体的免疫自稳。我们也发现在清洁环境(CL)中野生型小鼠体内Treg细胞的比例高于TLR4~(-/-)，TLR9~(-/-)小鼠，而在SPF环境中三种小鼠体内Treg的比例相当，均为清洁环境中TLR4~(-/-)，TLR9~(-/-)小鼠水平，但当TLR4和TLR9配体作用野生型小鼠后其体内Treg细胞比例升高。然而TLR信号调节CD4~+T细胞表达Foxp3的细胞和分子机制仍不为人所知。在本实验中，我们发现TLR4和TLR9信号激活后，体内出现一群具有调节功能的新型单核细胞亚群(Gr-1~(high)Ly-6C~(int))，该新型Gr-1~(high)Ly-6C~(int)单核细胞亚群参与诱导外周Treg的生成。TLR4和TLR9激动剂作用后，机体通过释放一氧化氮(NO)从骨髓动员一群Gr-1~(high)Ly-6C~(int)单核细胞入外周血同时上调其表达膜表面TGF-β(mTGF-β)。Gr-1~(high)Ly-6C~(int)单核细胞膜表面TGF-β可以促进β-catenin入核、活化STAT3、进而STAT3诱导CD4~+CD25-T细胞表达Foxp3。而与对照相比，β-catenin缺陷的CD4~+CD25-T细胞并不能在Gr-1~(high)Ly-6C~(int)单核细胞作用下分化为Treg细胞。另外，我们建立DSS诱导的小鼠炎症性肠病(IBD)模型，发现在清洁环境中TLR4~(-/-)、TLR9~(-/-)小鼠比野生型小鼠更易得IBD，而在SPF环境中TLR信号对DSS诱导的小鼠IBD的发生发展具有保护作用。因此，我们认为TLR信号的适度活化有助于保护宿主减少自身免疫性疾病的发生和发展；TLR信号活化通过诱导产生一群具有调节功能的新型单核细胞亚群，活化T细胞内β-catenin／STAT3信号，诱导CD4~+CD25-T前体细胞分化为Treg，从而控制自身免疫应答反应。
PartⅠFibronectin promotes NK cell survival viaβ-catenin pathway
Tissue microenvironment and stroma-derived extracellular matrix(ECM)molecules play important roles in the survival and differentiation of cells.Mouse naturalkiller(NK)cells usually die within 24 hours once isolated ex vivo.Exogenouscytokines such as interleukin(IL)-12 and IL-15 are required to maintain the survivaland activity of mouse NK cells cultured in vitro.However,whether and how ECMmolecules such as fibronectin can support the survival of NK cells remain unknown.Here we demonstrate that fibronectin,just like IL-15,can maintain survival of mouseNK cells in vitro.Furthermore,we show that fibronectin binds to the CDllb on NKcells,and then CD11b recruits and activates Src.Src can directly interact withβ-cateninand trigger nuclear translocation ofβ-catenin.The activation ofβ-catenin promotesERK phosphorylation,resulting in the increased expression of anti-apoptotic proteinBcl-2 which may contribute to the maintenance of NK cell survival.Consistently,fibronectin can not maintain the survival of CDllb negative NK cells andβ-catenin-deficient NK cells sorted from in vivo,and the number of NK cell isdramatically decreased in theβ-catenin-deficient mice.Therefore,fibronectin canmaintain survival of mouse NK cells by activating ERK and upregulating Bcl-2expression via CD11b/Src/β-catenin pathway.
PartⅡTLR 4,9 signals-recruited regulatory monocytes maintainhomeostasis of regulatory T cells through membrane bound TGF-βandβ-catenin pathway
Several Toll-like receptor(TLR)agonists play protective roles in the pathogenesisof autoimmune diseases and asthma.It has been found that constant exposure to lowconcentration of some TLR agonists contributes to the maintenance of an essentialnumber of CD4+Foxp3+regulatory T cell(Treg)in vivo,giving a reasonableexplanation for the protective role of TLR signals.However,the cellular and molecularmechanisms of TLR signals involved in regulating the expression of Foxp3 in CD4~+Tcells remain unclear up to now.Here,we demonstrate that a new population ofGr-1~(high)Ly-6C~(int)monocytes with regulatory function,triggered by TLR4,9 ligands,canpromot generation of CD4~+Foxp3~+Treg.TLR4,9 ligands could recruite Gr-1~(high)Ly-6C~(int)monocytes from bonce marrow via stimulating the release of NO and upregulatedexpression of membrane-bound TGF-βon Gr-1~(high)Ly-6C~(int)monocytes.Membrane-bound TGF-βon Gr-1~(high)Ly-6C~(int)monocytes induces Foxp3 expression in CD4~+CD25~-Tcells by activatingβ-catenin-dependent STAT3 pathway.Compared to wild-typeCD4~+CD25~-T cells,β-catenin~(-/-)CD4~+CD25~-T cells could not be induced to differentiateinto CD4~+Foxp3~+Treg by Gr-1~(high)Ly-6C~(int)monocytes.Furthermore,in clean condition,TLR4~(-/-)and TLR9~(-/-)mice acquire severer inflammatory bowel disease(IBD)after DSStreatment,while in SPF condition,TLR signals play a protective role in DSS-induceddevelopment of IBD.Thus,we conclude that TLR signals are required for controllingautoimmune responses viaβ-catenin/STAT3-dependent induction of Treg by inducinggeneration of a new subset of Gr-1~(high)Ly-6C~(int)regulatory monocytes.
组织微环境和细胞外基质分子在维持细胞生存促进细胞分化过程中具有重要作用。NK细胞是一类短寿命的细胞类型，尤其小鼠NK细胞分离后在体外存活时间更是少于24小时，因此需要在体外培养体系中加入外源性的细胞因子如IL-12、IL-15以维持小鼠NK细胞的生存。但是很多研究认为NK细胞的体内存活时间远远大于体外，表明体内不同组织微环境为NK细胞的生存提供了支持环境。但是细胞外基质分子如Fibronectin是否以及如何支持NK细胞的生存仍不为人所知。在本课题中，我们发现适当浓度的Fibronectin(10μg／ml)能在体外维持NK细胞的生存。
在探讨Fibronectin维持NK细胞生存的信号机制中，我们发现Fibronectin作用NK细胞后能够上调抗凋亡分子Bcl-2的表达。进一步研究发现，Fibronectin通过结合NK细胞表面的CD11b受体，募集并活化信号分子Src，Src作为β-catenin的上游信号分子，通过与β-catenin直接相互作用，导致β-catenin活化、入核。β-catenin的活化激活Erk分子，进而上调抗凋亡分子Bcl-2的表达，促进NK细胞的存活。同时，Fibronectin并不能维持CD11b阴性的NK细胞以及β-catenin缺陷的NK细胞的体外存活。因此，我们发现Fibronectin通过CD11b／Src／β-catenin途径活化ERK上调Bcl-2的表达从而维持NK细胞的生存。
第二部分TLR4和TLR9配体诱导的调节性单核细胞通过膜结
合型TGF-β和β-catenin通路诱导调节性T细胞的研究
调节性T细胞(Regulatory T cells，Treg)在抑制机体免疫反应和阻止有害的自身免疫应答中具有重要的作用。在免疫应答后期，Treg可以削弱效应性T细胞的功能，将免疫应答控制在一定限度内。许多流行病学研究以及实验研究提示一些Toll样受体(TLR)激动剂在自身免疫性疾病和哮喘的发病中具有保护作用。宿主持续性暴露于低剂量TLR激动剂后有助于维持体内一定数量的CD4~+FoxP3~+调节性T细胞，从而维持了机体的免疫自稳。我们也发现在清洁环境(CL)中野生型小鼠体内Treg细胞的比例高于TLR4~(-/-)，TLR9~(-/-)小鼠，而在SPF环境中三种小鼠体内Treg的比例相当，均为清洁环境中TLR4~(-/-)，TLR9~(-/-)小鼠水平，但当TLR4和TLR9配体作用野生型小鼠后其体内Treg细胞比例升高。然而TLR信号调节CD4~+T细胞表达Foxp3的细胞和分子机制仍不为人所知。在本实验中，我们发现TLR4和TLR9信号激活后，体内出现一群具有调节功能的新型单核细胞亚群(Gr-1~(high)Ly-6C~(int))，该新型Gr-1~(high)Ly-6C~(int)单核细胞亚群参与诱导外周Treg的生成。TLR4和TLR9激动剂作用后，机体通过释放一氧化氮(NO)从骨髓动员一群Gr-1~(high)Ly-6C~(int)单核细胞入外周血同时上调其表达膜表面TGF-β(mTGF-β)。Gr-1~(high)Ly-6C~(int)单核细胞膜表面TGF-β可以促进β-catenin入核、活化STAT3、进而STAT3诱导CD4~+CD25-T细胞表达Foxp3。而与对照相比，β-catenin缺陷的CD4~+CD25-T细胞并不能在Gr-1~(high)Ly-6C~(int)单核细胞作用下分化为Treg细胞。另外，我们建立DSS诱导的小鼠炎症性肠病(IBD)模型，发现在清洁环境中TLR4~(-/-)、TLR9~(-/-)小鼠比野生型小鼠更易得IBD，而在SPF环境中TLR信号对DSS诱导的小鼠IBD的发生发展具有保护作用。因此，我们认为TLR信号的适度活化有助于保护宿主减少自身免疫性疾病的发生和发展；TLR信号活化通过诱导产生一群具有调节功能的新型单核细胞亚群，活化T细胞内β-catenin／STAT3信号，诱导CD4~+CD25-T前体细胞分化为Treg，从而控制自身免疫应答反应。
PartⅠFibronectin promotes NK cell survival viaβ-catenin pathway
Tissue microenvironment and stroma-derived extracellular matrix(ECM)molecules play important roles in the survival and differentiation of cells.Mouse naturalkiller(NK)cells usually die within 24 hours once isolated ex vivo.Exogenouscytokines such as interleukin(IL)-12 and IL-15 are required to maintain the survivaland activity of mouse NK cells cultured in vitro.However,whether and how ECMmolecules such as fibronectin can support the survival of NK cells remain unknown.Here we demonstrate that fibronectin,just like IL-15,can maintain survival of mouseNK cells in vitro.Furthermore,we show that fibronectin binds to the CDllb on NKcells,and then CD11b recruits and activates Src.Src can directly interact withβ-cateninand trigger nuclear translocation ofβ-catenin.The activation ofβ-catenin promotesERK phosphorylation,resulting in the increased expression of anti-apoptotic proteinBcl-2 which may contribute to the maintenance of NK cell survival.Consistently,fibronectin can not maintain the survival of CDllb negative NK cells andβ-catenin-deficient NK cells sorted from in vivo,and the number of NK cell isdramatically decreased in theβ-catenin-deficient mice.Therefore,fibronectin canmaintain survival of mouse NK cells by activating ERK and upregulating Bcl-2expression via CD11b/Src/β-catenin pathway.
PartⅡTLR 4,9 signals-recruited regulatory monocytes maintainhomeostasis of regulatory T cells through membrane bound TGF-βandβ-catenin pathway
Several Toll-like receptor(TLR)agonists play protective roles in the pathogenesisof autoimmune diseases and asthma.It has been found that constant exposure to lowconcentration of some TLR agonists contributes to the maintenance of an essentialnumber of CD4+Foxp3+regulatory T cell(Treg)in vivo,giving a reasonableexplanation for the protective role of TLR signals.However,the cellular and molecularmechanisms of TLR signals involved in regulating the expression of Foxp3 in CD4~+Tcells remain unclear up to now.Here,we demonstrate that a new population ofGr-1~(high)Ly-6C~(int)monocytes with regulatory function,triggered by TLR4,9 ligands,canpromot generation of CD4~+Foxp3~+Treg.TLR4,9 ligands could recruite Gr-1~(high)Ly-6C~(int)monocytes from bonce marrow via stimulating the release of NO and upregulatedexpression of membrane-bound TGF-βon Gr-1~(high)Ly-6C~(int)monocytes.Membrane-bound TGF-βon Gr-1~(high)Ly-6C~(int)monocytes induces Foxp3 expression in CD4~+CD25~-Tcells by activatingβ-catenin-dependent STAT3 pathway.Compared to wild-typeCD4~+CD25~-T cells,β-catenin~(-/-)CD4~+CD25~-T cells could not be induced to differentiateinto CD4~+Foxp3~+Treg by Gr-1~(high)Ly-6C~(int)monocytes.Furthermore,in clean condition,TLR4~(-/-)and TLR9~(-/-)mice acquire severer inflammatory bowel disease(IBD)after DSStreatment,while in SPF condition,TLR signals play a protective role in DSS-induceddevelopment of IBD.Thus,we conclude that TLR signals are required for controllingautoimmune responses viaβ-catenin/STAT3-dependent induction of Treg by inducinggeneration of a new subset of Gr-1~(high)Ly-6C~(int)regulatory monocytes.
引文
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[12] Timm, A. & Grosschedl, R. Wnt signaling in lymphopoiesis. Curr. Top. Microbiol.Immunol. 290, 225-252 (2005).
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[22] Dosen, G. et al. Wnt expression and canonical Wnt signaling in human bone marrow B lymphopoiesis. BMC. Immunol. 7, 13 (2006).
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