醫(yī)學(xué)免疫學(xué)課件：微小RNA181a在T細(xì)胞陽性選擇和陰性選擇中的作用

1、微小RNA181a在T細(xì)胞陽性選擇和陰性選擇中的作用背景相關(guān)資料介紹T細(xì)胞微小RNA（microRNA, miRNA）微小RNA對T細(xì)胞發(fā)育的作用微小RNA181a在T細(xì)胞陽性選擇和陰性選擇中的作用還需解決的問題背景相關(guān)介紹T細(xì)胞發(fā)育過程（1）圖片摘自/T-cells T細(xì)胞發(fā)育過程（2）圖片摘自/T-cells T細(xì)胞陽選陰選陽性選擇陰性選擇微小RNA基本介紹微小 RNA（MicroRNA，miRNA)是一類內(nèi)源性非編碼小分子RNA大概有22個左右核苷酸長能靶向結(jié)合mRNA、并在轉(zhuǎn)錄后水平上調(diào)控目的基因的表達(dá)在機(jī)體中發(fā)揮重要調(diào)節(jié)作用Bartel, D. P. (2004). MicroRNA

2、s: Genomics,Biogenesis, Mechanism, and Function. Cell 116, 281-297.微小RNA產(chǎn)生機(jī)制Bartel, D. P. (2004). MicroRNAs: Genomics,Biogenesis, Mechanism, and Function. Cell 116, 281-297.RNA聚合酶II催化細(xì)胞核內(nèi)編碼miRNA基因含有莖環(huán)結(jié)構(gòu)初級miRNA (pri-miRNA)Drosha酶作用前體miRNA(pre-miRNA)約22核苷酸長度雙鏈miRNA單鏈成熟miRNA同RNA誘導(dǎo)沉默復(fù)合體（ RNA-induced sil

3、encing complex,RISC） 結(jié)合轉(zhuǎn)運(yùn)蛋白exportin5轉(zhuǎn)運(yùn)Dicer酶剪切解鏈微小RNA作用機(jī)理通過自身5端末的長為6-8核苷酸的種子序列（seed sequences）與靶向mRNA的3端未翻譯域（3-untranslated regions 3-UTR）配對同一miRNA家族的不同miRNA可以有同樣的種子序列，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翻譯誘導(dǎo)mRNA降解縮短mRNA的polyA尾巴從而增加其的不穩(wěn)定性PS：最近也有研究顯示部分miRNA可以促進(jìn)mRNA翻譯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對T細(xì)胞發(fā)育的作用敲除Drosha/Dicer對T細(xì)胞發(fā)育影響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且抑制細(xì)胞凋亡對T細(xì)胞發(fā)育影響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且抑制細(xì)胞凋亡對T細(xì)胞發(fā)育影響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細(xì)胞發(fā)育中發(fā)揮作用的微小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細(xì)胞發(fā)育中發(fā)揮作用的微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細(xì)胞陽性選擇和陰性選擇中的作用為什么選擇微小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細(xì)胞發(fā)育中數(shù)量的變化Chen, C. Z., Li, L., Lodish, H.F

10、., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a對成熟T細(xì)胞TCR的影響激動劑（agonist）：和TCR結(jié)合最穩(wěn)定的pMHC復(fù)合體弱激動劑（weak agonist）：和TCR結(jié)合較不穩(wěn)定的pMHC復(fù)合體拮抗劑（antagonists）：不能激活T細(xì)胞翻譯，且阻止T細(xì)胞和激活劑反應(yīng)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對成熟T細(xì)胞TCR的影響Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a對成熟T細(xì)胞TCR的影響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對成熟T細(xì)胞TCR的影響Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a對成熟T細(xì)胞TCR的影響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對TCR的影響原因Chen, C. Z., Li, L., Lodish, H.F., and Bartel, D.P (2004). MicroRNAs Modulate Hematopoietic Lineage Differentiation. Science 303.微小RNA181a對TCR的影響原因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對TCR的影響原因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缺乏對T細(xì)胞陽選的影響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.用胚胎胸腺器官培養(yǎng)（fetal thymic organ culture , FTOC）微小RNA181a缺乏對T細(xì)胞陰選的影響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缺乏對T細(xì)胞陰選的影響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數(shù)量之間的關(guān)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.雙熒光蛋白報告檢測（ 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.還需解決的問題微小RNA調(diào)節(jié)的具體過程完善T細(xì)胞發(fā)育的具體過程完善參考文獻(xiàn)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