醫(yī)學免疫學課件：共抑制相關因子PD-1作用的主要機制

1、共抑制相關因子PD-1作用的主要機制背景免疫抑制機制腫瘤激活機制缺陷&前景背景免疫抑制機制腫瘤激活機制缺陷&前景背景T細胞活化的雙信號模型第一信號：特異性抗原識別第二信號：輔助信號共刺激 | 共抑制PD-1程序性死亡受體11992年發(fā)現(xiàn)小鼠凋亡的細胞中表達T細胞抗原受體、細胞因子誘導產(chǎn)生B細胞、單核細胞敲除自身免疫病人60%同源背景免疫抑制機制腫瘤激活機制缺陷&前景結構N段：免疫球蛋白易變區(qū)類似結構20個氨基酸的桿部跨膜區(qū)胞質尾部：有酪氨酸信號基序ITIM招募胞內的 SHP-2 ，磷酸化ITSMSHP1、SHP2的停泊位點改變時抑制作用消失結構ITIM、ITSMKelly-Ann Sheppa

2、rd , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 結構N段：免疫球蛋白易變區(qū)類似結構20個氨基酸的桿部跨膜區(qū)胞質尾部：有酪氨酸信

3、號基序ITIM招募胞內的 SHP-2 ，磷酸化ITSMSHP1、SHP2的停泊位點改變時抑制作用消失結構ITSMChemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. J Immunol 2004;173:945-54. /content/173/2/945.longSHP-1 and SHP-2 associate with ITSM of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell

4、activation. 通路1Kelly-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly

5、-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly-Ann Sheppard , Lori

6、 J. Fitz , Julie M. Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路1Kelly-Ann Sheppard , Lori J. Fitz , Julie M.

7、Lee, et al FEBS Letters , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Bio

8、l 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phatase activity while decreasing PTEN protein stability by inhibiting casein kiinase 2. 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Biol 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phata

9、se activity while decreasing PTEN protein stability by inhibiting casein kiinase 2. 通路2Patsoukis N, Li L, Sari D, Petkova V, Boussiotis VA. Mol Cell Biol 2013;33:3091-8. /pmc/articles/PMC3753920/PD-1 increases PTEN phos- phatase activity while decreasing PTEN protein stability by inhibiting casein k

10、iinase 2. 通路3Ras-MEK-ERKPatsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 2012;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 通路3Ras-MEK-ERKPatsoukis N, Brown J,

11、 Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 2012;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 通路3Ras-MEK-ERKKelly-Ann Sheppard , Lori J. Fitz , Julie M. Lee, et al FEBS Lette

12、rs , Volume 574, Issues 13 10 September 2004, Pages 3741/science/article/pii/S0014579304009779PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3f signalosome and downstream signaling to PKCh 通路3Ras-MEK-ERKPatsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA. Sci Signal 201

13、2;5:ra46. /content/5/230/ra46.longSelective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. 新陳代謝變化Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramm

14、ing by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.PD1減少葡萄糖運輸和利用抑制氨基酸的轉運和代謝誘發(fā)內源性脂肪分解氧化新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolys

15、is and fatty acid oxidation.新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化葡萄糖Patsoukis N, Bardhan K, Chatterjee P, et al. Nat

16、 Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化脂肪酸Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming b

17、y inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.新陳代謝變化脂肪酸Patsoukis N, Bardhan K, Chatterjee P, et al. Nat Commun 2015;6:6692. /articles/ncomms7692PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.背景免疫抑制機制腫瘤激活

18、機制缺陷前景機制-適應性免疫抵抗Taube, J. M. et al. J. Sci Transl Med. 4, 127ra37 (2012). /content/4/127/127ra37.longColocalization of in ammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. 常用藥物Joel Sunshine, Janis M Taube Current Opinion in