1、衰老對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響1234背景衰老以及正常T細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)內(nèi)環(huán)境的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響細(xì)胞膜的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響細(xì)胞內(nèi)信號分子的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響提綱.內(nèi)環(huán)境細(xì)胞膜細(xì)胞內(nèi)5未來展望1背景衰老以及正常T細(xì)胞的信號轉(zhuǎn)導(dǎo)衰老與免疫系統(tǒng)312抵御感染自身監(jiān)視免疫調(diào)節(jié)1.背景4T細(xì)胞介導(dǎo)的特異性免疫1.背景正常T細(xì)胞信號轉(zhuǎn)導(dǎo)通路3.Larbi, A., et al., Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res Rev, 2011. 10(3)

2、: p. 370-8.激活S6kinase和PKC，抑制p21和GSK32內(nèi)環(huán)境內(nèi)環(huán)境的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響細(xì)胞因子和激素含量2.細(xì)胞內(nèi) 312腫瘤壞死因子IL-6IL-334GH腫瘤壞死因子2.內(nèi)環(huán)境picture63.Larbi, A., et al., Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res Rev, 2011. 10(3): p. 370-8.乙酰半胱氨酸，體內(nèi)谷胱甘肽的補(bǔ)充物可以緩解通過產(chǎn)生活性氧中間產(chǎn)物作用TCRzeta鏈，降低TCR/CD3

3、復(fù)合物的表達(dá)減弱ZAP-70，LAT和PLC的磷酸化降低CD28的表達(dá)IL-62.內(nèi)環(huán)境5.Goronzy, J.J., et al., Signaling pathways in aged T cells - a reflection of T cell differentiation, cell senescence and host environment. Semin Immunol, 2012. 24(5): p. 365-72.IL-332.內(nèi)環(huán)境 6.Kuswanto, W., et al., Poor Repair of Skeletal Muscle in Aging Mic

4、e Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity, 2016. 44(2): p. 355-67.骨骼肌細(xì)胞的修復(fù)需要Foxp3陽性CD4陽性的T細(xì)胞聚集IL-33對調(diào)節(jié)性T細(xì)胞的自身穩(wěn)定有關(guān)。2.內(nèi)環(huán)境 7.Schiering, C., et al., The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature, 2014. 513(7519):

5、p. 564-8.IL-33通過與Treg上的受體ST2結(jié)合，促進(jìn)TGF-1介導(dǎo)的信號轉(zhuǎn)導(dǎo)通路，激活調(diào)節(jié)性T細(xì)胞的分化沒有TGF-1時(shí)，IL-33也不能增加Foxp3陽性T細(xì)胞的數(shù)量和比例。TGF-1存在時(shí)，IL-33是能明顯上調(diào)Foxp3陽性T細(xì)胞的數(shù)量和比例GH2.內(nèi)環(huán)境/figure/6163824_fig2_Fig-2-Growth-hormone-mediated-JAKSTAT-signal-transduction-GH-activates-several細(xì)胞因子和激素含量2.內(nèi)環(huán)境 312腫瘤壞死因子 三個(gè)作用通路IL-6 SOCS3STATIL-33 ST2TGF14GH J

6、AKSTAT，IGF-13細(xì)胞膜細(xì)胞膜受體的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響123NK細(xì)胞受體細(xì)胞膜 .細(xì)胞因子和趨化因子有關(guān)受體脂筏NK細(xì)胞受體3.細(xì)胞膜14.Pereira, B.I. and A.N. Akbar, Convergence of Innate and Adaptive Immunity during Human Aging. Front Immunol, 2016. 7: p. 445.衰老CD8陽性的T細(xì)胞中NK細(xì)胞所特有的受體的增多Innate-like T cell含量減少， CD8陽性的T細(xì)胞增多T細(xì)胞增殖能力減弱分泌IFN-以及TNF-CD8陽性的T細(xì)胞可以單獨(dú)對NK

7、G2D反應(yīng)，而沒有TCR的介導(dǎo)高度分化的CD4陽性T細(xì)胞也會(huì)表達(dá)NKG2D細(xì)胞因子也會(huì)促進(jìn)CD8陽性T細(xì)胞表達(dá)NK細(xì)胞的受體整合固有免疫和特異性免疫細(xì)胞因子和趨化因子有關(guān)受體3. 細(xì)胞膜312IL-7R表達(dá)降低CX3CR1表達(dá)量增高CCR2，CCR6和CCR7表達(dá)量降低4CXCR4表達(dá)量增高3.細(xì)胞膜16.Heigele, A., et al., Increased susceptibility of CD4+ T cells from elderly individuals to HIV-1 infection and apoptosis is associated with reduced

8、 CD4 and enhanced CXCR4 and FAS surface expression levels. Retrovirology, 2015. 12: p. 86.細(xì)胞因子和趨化因子有關(guān)受體老年人的CD4陽性的T細(xì)胞表面上CD4的表達(dá)量降低，CXCR4和FAS的表達(dá)量都增高年老的人T細(xì)胞更容易受HIV-1病毒感染。3.細(xì)胞膜脂筏4.Fulop, T., et al., Cellular signaling in the aging immune system. Curr Opin Immunol, 2014. 29: p. 105-11.脂筏基本組成成分包括Lck，Cbp/PA

9、GTCR，CD28，IL-2R，LAT和PI3K在激活時(shí)聚集過來衰老的CD4陽性T細(xì)胞中脂筏很少聚集在一起聚集和激活Lck，LAT和SHP-1都發(fā)生了改變脂筏上的CD28和IL-2都明顯減少了膽固醇的代謝發(fā)生了改變受體的改變量和脂筏3.細(xì)胞膜 312NK細(xì)胞受體 固有免疫和特異性免疫整合細(xì)胞因子和趨化因子有關(guān)受體 CXCR4脂筏 膽固醇的代謝4細(xì)胞內(nèi)細(xì)胞內(nèi)信號分子的改變對T細(xì)胞信號轉(zhuǎn)導(dǎo)的影響4. 細(xì)胞內(nèi)312MAPkinase信號轉(zhuǎn)導(dǎo)通路Lckp384其他miR-181a-Dusp4.細(xì)胞內(nèi)5.Goronzy, J.J., et al., Signaling pathways in aged

10、T cells - a reflection of T cell differentiation, cell senescence and host environment. Semin Immunol, 2012. 24(5): p. 365-72.miR-181a在胸腺中含量較高。隨著T細(xì)胞的分化，含量逐漸減少。miR-181a含量的減少與機(jī)體避免自身免疫病有關(guān)。Dusp5和Dusp6會(huì)去磷酸化MAPkinase信號通路中的信號分子miR-181a可以調(diào)控。Lck4.細(xì)胞內(nèi)10.Le Page, A., et al., Downregulation of inhibitory SRC ho

11、mology 2 domain-containing phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly. Cell Commun Signal, 2014. 12: p. 211. Lanna, A., et al., The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat Immunol, 2014. 15(10): p.

12、 965-72CD45去磷酸化ROS增高CD45活性降低SHP-1表達(dá)量增高Csk會(huì)磷酸化Lck并抑制其活性。CD45上的PTPase會(huì)去磷酸化Lck從而激活其活性。在細(xì)胞中SHP-1會(huì)作用于Lck，降低其活性。4.細(xì)胞內(nèi)12.Henson, S.M., et al., Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol, 2015. 45(5): p. 1441-51p38衰老T

13、細(xì)胞中，p38 MAP kinase不受TCR介導(dǎo)的信號通路活化自發(fā)激活A(yù)MPKp38結(jié)合到支架蛋白TAB1p38自身磷酸化。降低TCR信號轉(zhuǎn)導(dǎo)通路中關(guān)鍵的信號分子的表達(dá)量。其他信號分子4.細(xì)胞內(nèi)13. Fann, M., et al., Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev, 2005. 205: p. 190-206.4. 細(xì)胞內(nèi)312MAPkinase信號轉(zhuǎn)導(dǎo)通路 Mir-181a-

14、DUSPLck Csk/PAG/CD45環(huán) SHP-1P38 AMPKTAB1自我磷酸化4其他 CD28陰性與CD28陽性CD8T細(xì)胞信號分子表達(dá)量發(fā)生改變展望312內(nèi)環(huán)境 IL-33細(xì)胞膜 CXCR4 細(xì)胞內(nèi) SHP-1 p38Reference(1) 1.張帆等, T細(xì)胞抗原受體復(fù)合體信號轉(zhuǎn)導(dǎo)及其與疾病關(guān)系的研究進(jìn)展. 中國醫(yī)藥生物技術(shù), 2007(03): 第215-217頁. 2.張宏娟與王躍, T細(xì)胞衰老及分子機(jī)制的研究進(jìn)展. 國外醫(yī)學(xué)（老年醫(yī)學(xué)分冊）, 2005. 26(2): 第88-91,95頁. 3.Larbi, A., et al., Impact of age on T

15、cell signaling: a general defect or specific alterations? Ageing Res Rev, 2011. 10(3): p. 370-8. 4.Fulop, T., et al., Cellular signaling in the aging immune system. Curr Opin Immunol, 2014. 29: p. 105-11. 5.Goronzy, J.J., et al., Signaling pathways in aged T cells - a reflection of T cell differenti

16、ation, cell senescence and host environment. Semin Immunol, 2012. 24(5): p. 365-72. 6.Kuswanto, W., et al., Poor Repair of Skeletal Muscle in Aging Mice Reflects a Defect in Local, Interleukin-33-Dependent Accumulation of Regulatory T Cells. Immunity, 2016. 44(2): p. 355-67. 7.Schiering, C., et al.,

17、 The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature, 2014. 513(7519): p. 564-8. 8.Mahesh, S. and F. Kaskel, Growth hormone axis in chronic kidney disease. Pediatr Nephrol, 2008. 23(1): p. 41-8. 9.Chaudhry, M.S., et al., Thymus: the next (re)generation. Immunol Rev, 2016.

18、271(1): p. 56-71.10.Le Page, A., et al., Downregulation of inhibitory SRC homology 2 domain-containing phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly. Cell Commun Signal, 2014. 12: p. 2.11.Lanna, A., et al., The kinase p38 activated by the metabolic regulator AMPK and scaffol

19、d TAB1 drives the senescence of human T cells. Nat Immunol, 2014. 15(10): p. 965-72.12.Henson, S.M., et al., Blockade of PD-1 or p38 MAP kinase signaling enhances senescent human CD8(+) T-cell proliferation by distinct pathways. Eur J Immunol, 2015. 45(5): p. 1441-51.Reference(2)13.Fann, M., et al., Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging. Immunol Rev, 2005. 205: p. 190-206.14.Pereira, B.I.