医学免疫学课件：微小RNA181a在T细胞阳性选择和阴性选择中的作用

1、微小RNA181a在T细胞阳性选择和阴性选择中的作用背景相关资料介绍T细胞微小RNA（microRNA, miRNA）微小RNA对T细胞发育的作用微小RNA181a在T细胞阳性选择和阴性选择中的作用还需解决的问题背景相关介绍T细胞发育过程（1）图片摘自/T-cells T细胞发育过程（2）图片摘自/T-cells T细胞阳选阴选阳性选择阴性选择微小RNA基本介绍微小 RNA（MicroRNA，miRNA)是一类内源性非编码小分子RNA大概有22个左右核苷酸长能靶向结合mRNA、并在转录后水平上调控目的基因的表达在机体中发挥重要调节作用Bartel, D. P. (2004). MicroRNA

2、s: Genomics,Biogenesis, Mechanism, and Function. Cell 116, 281-297.微小RNA产生机制Bartel, D. P. (2004). MicroRNAs: Genomics,Biogenesis, Mechanism, and Function. Cell 116, 281-297.RNA聚合酶II催化细胞核内编码miRNA基因含有茎环结构初级miRNA (pri-miRNA)Drosha酶作用前体miRNA(pre-miRNA)约22核苷酸长度双链miRNA单链成熟miRNA同RNA诱导沉默复合体（ RNA-induced sil

3、encing complex,RISC） 结合转运蛋白exportin5转运Dicer酶剪切解链微小RNA作用机理通过自身5端末的长为6-8核苷酸的种子序列（seed sequences）与靶向mRNA的3端未翻译域（3-untranslated regions 3-UTR）配对同一miRNA家族的不同miRNA可以有同样的种子序列，但其的下游部分不同D.R., P. K. a. S. (2013). microRNA regulation of T lymphocyte immunity: modulation of molecular networks responsible for T

4、cell activation, differentiation and development. Crit Rev Immuno 33: 435-476.微小RNA功能阻止mRNA翻译诱导mRNA降解缩短mRNA的polyA尾巴从而增加其的不稳定性PS：最近也有研究显示部分miRNA可以促进mRNA翻译D.R., P. K. a. S. (2013). microRNA regulation of T lymphocyte immunity: modulation of molecular networks responsible for T cell activation, differe

5、ntiation and development. Crit Rev Immuno 33: 435-476.Fabian, M. R., et al. (2010). Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79: 351-379.微小RNA对T细胞发育的作用敲除Drosha/Dicer对T细胞发育影响Chong, M. M., et al. (2010). Canonical and alternate functions of the microRNA biogenesis ma

6、chinery. Genes Dev 24(17): 1951-1960.敲除Dicer且抑制细胞凋亡对T细胞发育影响Rupp, L. J., et al. (2014). The microRNA biogenesis machinery modulates lineage commitment during alphabeta T cell development. J Immunol 193(8): 4032-4042.敲除Dicer且抑制细胞凋亡对T细胞发育影响Rupp, L. J., et al. (2014). The microRNA biogenesis machinery m

7、odulates lineage commitment during alphabeta T cell development. J Immunol 193(8): 4032-4042.在T细胞发育中发挥作用的微小RNASaki.N, A. S., Soleimani.M, Hajizamani.S , Shahjahani.M, Kast.R. E., Mortazavi,Y (2015). Involvement of MicroRNA in T-Cell Differentiation and Malignancy. IJHOSCR 9.在T细胞发育中发挥作用的微RNASaki.N, A

8、. S., Soleimani.M, Hajizamani.S , Shahjahani.M, Kast.R. E., Mortazavi,Y (2015). Involvement of MicroRNA in T-Cell Differentiation and Malignancy. IJHOSCR 9.微小RNA181a在T细胞阳性选择和阴性选择中的作用为什么选择微小RNA181a “miR-181 was very strongly expressed in the thymus, the primary lymphoid organ, which mainly contains T

9、 lymphocytes. It was also strongly expressed in the brain and lung and was detectable in bone marrow and the spleen. ”Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a在T细胞发育中数量的变化Chen, C. Z., Li, L., Lodish, H.F

10、., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对成熟T细胞TCR的影响激动剂（agonist）：和TCR结合最稳定的pMHC复合体弱激动剂（weak agonist）：和TCR结合较不稳定的pMHC复合体拮抗剂（antagonists）：不能激活T细胞翻译，且阻止T细胞和激活剂反应Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulat

11、e Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对成熟T细胞TCR的影响Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对成熟T细胞TCR的影响Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulat

12、e Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对成熟T细胞TCR的影响Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对成熟T细胞TCR的影响Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulat

13、e Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对TCR的影响原因Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a对TCR的影响原因Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hema

14、topoietic Lineage Differentiation. Science 303.微小RNA181a对TCR的影响原因Sonkoly, E., et al. (2008). MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Semin Cancer Biol 18(2): 131-140.微小RNA181a缺乏对T细胞阳选的影响Li, Q. J., et al. (2007). miR-181a is an intrinsic mod

15、ulator of T cell sensitivity and selection. Cell 129(1): 147-161.用胚胎胸腺器官培养（fetal thymic organ culture , FTOC）微小RNA181a缺乏对T细胞阴选的影响Li, Q. J., et al. (2007). miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129(1): 147-161.微小RNA181a缺乏对T细胞阴选的影响Ebert, P. J., et al. (2009). An

16、endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat Immunol 10(11): 1162-1169.TCR活性和mi181a数量之间的关系Ebert, P. J., et al. (2009). An endogenous positively selecting peptide enhances mature T cell responses and becom

17、es an autoantigen in the absence of microRNA miR-181a. Nat Immunol 10(11): 1162-1169.miR181a同CD69的作用Blevins, R., et al. (2015). microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes. PLoS Genet 11(2): e1005020.双荧光蛋白报告检测（ dual fluorescence rep

18、orter system）miR181a同CD69的作用Blevins, R., et al. (2015). microRNAs regulate cell-to-cell variability of endogenous target gene expression in developing mouse thymocytes. PLoS Genet 11(2): e1005020.还需解决的问题微小RNA调节的具体过程完善T细胞发育的具体过程完善参考文献Bartel, D. P. (2004). MicroRNAs: Genomics,Biogenesis, Mechanism, an

19、d Function. Cell 116, 281-297.Johanson, T. M., et al. (2014). The role of microRNAs in lymphopoiesis. Int J Hematol 100(3): 246-253.D.R., P. K. a. S. (2013). microRNA regulation of T lymphocyte immunity: modulation of molecular networks responsible for T cell activation, differentiation and developm

20、ent. Crit Rev Immuno 33: 435-476.Fabian, M. R., et al. (2010). Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 79: 351-379.Chong, M. M., et al. (2010). Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev 24(17): 1951-1960.Rupp, L. J., et al.

21、(2014). The microRNA biogenesis machinery modulates lineage commitment during alphabeta T cell development. J Immunol 193(8): 4032-4042.Saki.N, A. S., Soleimani.M, Hajizamani.S , Shahjahani.M, Kast.R. E., Mortazavi,Y (2015). Involvement of MicroRNA in T-Cell Differentiation and Malignancy. IJHOSCR 9

22、.Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.Li, Q. J., et al. (2007). miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129(1): 147-161.Sonkoly, E., et al. (2008). MicroRNAs and immunity: novel players in the regulation of