医学免疫学课件：衰老对T细胞信号转导的影响

1、衰老对T细胞信号转导的影响1234背景衰老以及正常T细胞内信号转导内环境的改变对T细胞信号转导的影响细胞膜的改变对T细胞信号转导的影响细胞内信号分子的改变对T细胞信号转导的影响提纲.内环境细胞膜细胞内5未来展望1背景衰老以及正常T细胞的信号转导衰老与免疫系统312抵御感染自身监视免疫调节1.背景4T细胞介导的特异性免疫1.背景正常T细胞信号转导通路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内环境内环境的改变对T细胞信号转导的影响细胞因子和激素含量2.细胞内 312肿瘤坏死因子IL-6IL-334GH肿瘤坏死因子2.内环境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，体内谷胱甘肽的补充物可以缓解通过产生活性氧中间产物作用TCRzeta链，降低TCR/CD3

3、复合物的表达减弱ZAP-70，LAT和PLC的磷酸化降低CD28的表达IL-62.内环境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.内环境 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.骨骼肌细胞的修复需要Foxp3阳性CD4阳性的T细胞聚集IL-33对调节性T细胞的自身稳定有关。2.内环境 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通过与Treg上的受体ST2结合，促进TGF-1介导的信号转导通路，激活调节性T细胞的分化没有TGF-1时，IL-33也不能增加Foxp3阳性T细胞的数量和比例。TGF-1存在时，IL-33是能明显上调Foxp3阳性T细胞的数量和比例GH2.内环境/figure/6163824_fig2_Fig-2-Growth-hormone-mediated-JAKSTAT-signal-transduction-GH-activates-several细胞因子和激素含量2.内环境 312肿瘤坏死因子 三个作用通路IL-6 SOCS3STATIL-33 ST2TGF14GH J

6、AKSTAT，IGF-13细胞膜细胞膜受体的改变对T细胞信号转导的影响123NK细胞受体细胞膜 .细胞因子和趋化因子有关受体脂筏NK细胞受体3.细胞膜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阳性的T细胞中NK细胞所特有的受体的增多Innate-like T cell含量减少， CD8阳性的T细胞增多T细胞增殖能力减弱分泌IFN-以及TNF-CD8阳性的T细胞可以单独对NK

7、G2D反应，而没有TCR的介导高度分化的CD4阳性T细胞也会表达NKG2D细胞因子也会促进CD8阳性T细胞表达NK细胞的受体整合固有免疫和特异性免疫细胞因子和趋化因子有关受体3. 细胞膜312IL-7R表达降低CX3CR1表达量增高CCR2，CCR6和CCR7表达量降低4CXCR4表达量增高3.细胞膜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.细胞因子和趋化因子有关受体老年人的CD4阳性的T细胞表面上CD4的表达量降低，CXCR4和FAS的表达量都增高年老的人T细胞更容易受HIV-1病毒感染。3.细胞膜脂筏4.Fulop, T., et al., Cellular signaling in the aging immune system. Curr Opin Immunol, 2014. 29: p. 105-11.脂筏基本组成成分包括Lck，Cbp/PA

9、GTCR，CD28，IL-2R，LAT和PI3K在激活时聚集过来衰老的CD4阳性T细胞中脂筏很少聚集在一起聚集和激活Lck，LAT和SHP-1都发生了改变脂筏上的CD28和IL-2都明显减少了胆固醇的代谢发生了改变受体的改变量和脂筏3.细胞膜 312NK细胞受体 固有免疫和特异性免疫整合细胞因子和趋化因子有关受体 CXCR4脂筏 胆固醇的代谢4细胞内细胞内信号分子的改变对T细胞信号转导的影响4. 细胞内312MAPkinase信号转导通路Lckp384其他miR-181a-Dusp4.细胞内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在胸腺中含量较高。随着T细胞的分化，含量逐渐减少。miR-181a含量的减少与机体避免自身免疫病有关。Dusp5和Dusp6会去磷酸化MAPkinase信号通路中的信号分子miR-181a可以调控。Lck4.细胞内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表达量增高Csk会磷酸化Lck并抑制其活性。CD45上的PTPase会去磷酸化Lck从而激活其活性。在细胞中SHP-1会作用于Lck，降低其活性。4.细胞内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、细胞中，p38 MAP kinase不受TCR介导的信号通路活化自发激活AMPKp38结合到支架蛋白TAB1p38自身磷酸化。降低TCR信号转导通路中关键的信号分子的表达量。其他信号分子4.细胞内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. 细胞内312MAPkinase信号转导通路 Mir-181a-

14、DUSPLck Csk/PAG/CD45环 SHP-1P38 AMPKTAB1自我磷酸化4其他 CD28阴性与CD28阳性CD8T细胞信号分子表达量发生改变展望312内环境 IL-33细胞膜 CXCR4 细胞内 SHP-1 p38Reference(1) 1.张帆等, T细胞抗原受体复合体信号转导及其与疾病关系的研究进展. 中国医药生物技术, 2007(03): 第215-217页. 2.张宏娟与王跃, T细胞衰老及分子机制的研究进展. 国外医学（老年医学分册）, 2005. 26(2): 第88-91,95页. 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.