PD-1/PD-L1通路在哮喘发病机制中的研究进展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

黄艺林 ,  高金明

中国医学科学院北京协和医学院北京协和医院呼吸与危重症医学科（北京 100730）;

Corresponding author：

高金明, Email: gao.jin.ming@hotmail.com

Keywords：

DOI：

10.7507/1671-6205.202302045

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Citation： 黄艺林, 高金明. PD-1/PD-L1通路在哮喘发病机制中的研究进展. Chinese Journal of Respiratory and Critical Care Medicine, 2023, 22(8): 591-595. doi: 10.7507/1671-6205.202302045 Copy

1.	中华医学会呼吸病学分会哮喘学组. 支气管哮喘防治指南(2020年版). 中华结核和呼吸杂志, 2020, 43(12): 1023-1048.
2.	Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med, 1999, 160(3): 1001-1008.
3.	Pichavant M, Charbonnier AS, Taront S, et al. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J Allergy Clin Immunol, 2005, 115(4): 771-778.
4.	Paplinska-Goryca M, Misiukiewicz-Stepien P, Proboszcz M, et al. The expressions of TSLP, IL-33, and IL-17A in monocyte derived dendritic cells from asthma and COPD patients are related to epithelial–macrophage interactions. Cells, 2020, 9(9): 1944.
5.	Castellanos CA, Ren X, Gonzalez SL, et al. Lymph node-resident dendritic cells drive TH2 cell development involving MARCH1. Sci Immunol, 2021, 6(64): eabh0707.
6.	Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 2000, 192(7): 1027-1034.
7.	Galván Morales MA, Montero-Vargas JM, Vizuet-de-Rueda JC, et al. New insights into the role of PD-1 and its ligands in allergic disease. Int J Mol Sci, 2021, 22(21): 11898.
8.	Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
9.	Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol, 2004, 173(2): 945-954.
10.	Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999, 5(12): 1365-1369.
11.	Sugiura D, Maruhashi T, Okazaki IM, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science, 2019, 364(6440): 558-566.
12.	Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 2002, 8(8): 793-800.
13.	Reck M, Remon J, Hellmann MD. First-line immunotherapy for non-small-cell lung cancer. J Clin Oncol, 2022, 40(6): 586-597.
14.	Schönrich G, Raftery MJ. The PD-1/PD-L1 axis and virus infections: a delicate balance. Front Cell Infect Microbiol, 2019, 9: 207.
15.	Matsuda K, Miyoshi H, Hiraoka K, et al. Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis. Clin Exp Med, 2018, 18(4): 487-494.
16.	Matsumoto K, Inoue H, Nakano T, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol, 2004, 172(4): 2530-2541.
17.	钱美芳, 张艳, 尤倩, 等. 急性支气管哮喘病人外周血程序性死亡因子-1及其配体的表达. 安徽医药, 2022, 26(10): 2005-2009.
18.	蔡传旭, 刘晓清, 胡海圣, 等. 过敏性疾病患者外周血可溶性PD-L1的表达及意义. 实用医学杂志, 2018, 34(18): 3036-3040.
19.	Bratke K, Fritz L, Nokodian F, et al. Differential regulation of PD-1 and its ligands in allergic asthma. Clin Exp Allergy, 2017, 47(11): 1417-1425.
20.	McAlees JW, Lajoie S, Dienger K, et al. Differential control of CD4+ T cell subsets by the PD-1/PD-L1 axis in allergic asthma. Eur J Immunol, 2015, 45(4): 1019-1029.
21.	Wang SH, Zissler UM, Buettner M, et al. An exhausted phenotype of TH2 cells is primed by allergen exposure, but not reinforced by allergen-specific immunotherapy. Allergy, 2021, 76(9): 2827-2839.
22.	Ren YY, Dong HT, Liao JY, et al. The expression and function of programmed death-ligand 1 and related cytokines in neutrophilic asthma. Ann Transl Med, 2021, 9(23): 1727.
23.	Douwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax, 2002, 57(7): 643-648.
24.	Wang WB, Yen ML, Liu KJ, et al. Interleukin-25 mediates transcriptional control of PD-L1 via STAT3 in multipotent human mesenchymal stromal cells (hMSCs) to suppress Th17 responses. Stem Cell Reports, 2015, 5(3): 392-404.
25.	Helou DG, Quach C, Fung M, et al. Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells. J Allergy Clin Immunol, 2022: S0091674922010491.
26.	Chang WS, Kim JY, Kim YJ, et al. Cutting edge: programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol, 2008, 181(10): 6707-6710.
27.	Akbari O, Stock P, Singh AK, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunology, 2010, 3(1): 81-91.
28.	Hammad H, Lambrecht BN. The basic immunology of asthma. Cell, 2021, 184(6): 1469-1485.
29.	Helou DG, Shafiei-Jahani P, Lo R, et al. PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity. Nat Commun, 2020, 11(1): 3998.
30.	Dahlgren MW, Jones SW, Cautivo KM, et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity, 2019, 50(3): 707-722. e6.
31.	Taylor S, Huang Y, Mallett G, et al. PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J Exp Med, 2017, 214(6): 1663-1678.
32.	Schwartz C, Khan AR, Floudas A, et al. ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control. J Exp Med, 2017, 214(9): 2507-2521.
33.	Shen C, Hupin C, Froidure A, et al. Impaired ICOSL in human myeloid dendritic cells promotes Th2 responses in patients with allergic rhinitis and asthma. Clin Exp Allergy, 2014, 44(6): 831-841.
34.	Kool M, van Nimwegen M, Willart MAM, et al. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol, 2009, 183(2): 1074-1082.
35.	Zhang X, Lewkowich IP, Köhl G, et al. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol, 2009, 182(8): 5123-5130.
36.	Wang L, Pino-Lagos K, de Vries VC, et al. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A, 2008, 105(27): 9331-9336.
37.	Lin CL, Huang HM, Hsieh CL, et al. Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice. Immunology, 2019, 156(2): 199-212.
38.	Girodet PO, Nguyen D, Mancini JD, et al. Alternative macrophage activation is increased in asthma. Am J Respir Cell Mol Biol, 2016, 55(4): 467-475.
39.	Hamano S, Matsumoto K, Tonai K, et al. Effects of corticosteroid plus long-acting beta2-agonist on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice. J Inflamm (Lond), 2017, 14: 2.
40.	Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol, 2002, 169(10): 5538-5545.
41.	Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A, 2003, 100(9): 5336-5341.
42.	Roche WR, Beasley R, Williams JH, et al. Subepithelial fibrosis in the bronchi of asthmatics. Lancet, 1989, 1(8637): 520-524.
43.	Mostaço-Guidolin LB, Osei ET, Ullah J, et al. Defective fibrillar collagen organization by fibroblasts contributes to airway remodeling in asthma. Am J Respir Crit Care Med, 2019, 200(4): 431-443.
44.	Celada LJ, Kropski JA, Herazo-Maya JD, et al. PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci Transl Med, 2018, 10(460): eaar8356.
45.	Afroj T, Mitsuhashi A, Ogino H, et al. Blockade of PD-1/PD-L1 pathway enhances the antigen-presenting capacity of fibrocytes. J Immunol, 2021, 206(6): 1204-1214.
46.	Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2(3): 261-268.
47.	Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): ra46.
48.	Strazza M, Adam K, Lerrer S, et al. SHP2 targets ITK downstream of PD-1 to inhibit T cell function. Inflammation, 2021, 44(4): 1529-1539.
49.	Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Letters, 2004, 574(1-3): 37-41.
50.	Fanelli G, Romano M, Nova-Lamperti E, et al. PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLoS Biol, 2021, 19(4): e3001199.
51.	Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med, 2006, 203(3): 755-766.
52.	Constant S, Pfeiffer C, Woodard A, et al. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med, 1995, 182(5): 1591-1596.
53.	Amarnath S, Mangus CW, Wang JCM, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med, 2011, 3(111): 111ra120-111ra120.
54.	Yang K, Shrestha S, Zeng H, et al. T cell exit from quiescence and differentiation into Th2 cells depend on raptor-mTORC1-mediated metabolic reprogramming. immunity, 2013, 39(6): 1043-1056.

1. 中华医学会呼吸病学分会哮喘学组. 支气管哮喘防治指南(2020年版). 中华结核和呼吸杂志, 2020, 43(12): 1023-1048.
2. Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med, 1999, 160(3): 1001-1008.
3. Pichavant M, Charbonnier AS, Taront S, et al. Asthmatic bronchial epithelium activated by the proteolytic allergen Der p 1 increases selective dendritic cell recruitment. J Allergy Clin Immunol, 2005, 115(4): 771-778.
4. Paplinska-Goryca M, Misiukiewicz-Stepien P, Proboszcz M, et al. The expressions of TSLP, IL-33, and IL-17A in monocyte derived dendritic cells from asthma and COPD patients are related to epithelial–macrophage interactions. Cells, 2020, 9(9): 1944.
5. Castellanos CA, Ren X, Gonzalez SL, et al. Lymph node-resident dendritic cells drive TH2 cell development involving MARCH1. Sci Immunol, 2021, 6(64): eabh0707.
6. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med, 2000, 192(7): 1027-1034.
7. Galván Morales MA, Montero-Vargas JM, Vizuet-de-Rueda JC, et al. New insights into the role of PD-1 and its ligands in allergic disease. Int J Mol Sci, 2021, 22(21): 11898.
8. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
9. Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol, 2004, 173(2): 945-954.
10. Dong H, Zhu G, Tamada K, et al. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med, 1999, 5(12): 1365-1369.
11. Sugiura D, Maruhashi T, Okazaki IM, et al. Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses. Science, 2019, 364(6440): 558-566.
12. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med, 2002, 8(8): 793-800.
13. Reck M, Remon J, Hellmann MD. First-line immunotherapy for non-small-cell lung cancer. J Clin Oncol, 2022, 40(6): 586-597.
14. Schönrich G, Raftery MJ. The PD-1/PD-L1 axis and virus infections: a delicate balance. Front Cell Infect Microbiol, 2019, 9: 207.
15. Matsuda K, Miyoshi H, Hiraoka K, et al. Clinicopathological value of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression in synovium of patients with rheumatoid arthritis. Clin Exp Med, 2018, 18(4): 487-494.
16. Matsumoto K, Inoue H, Nakano T, et al. B7-DC regulates asthmatic response by an IFN-gamma-dependent mechanism. J Immunol, 2004, 172(4): 2530-2541.
17. 钱美芳, 张艳, 尤倩, 等. 急性支气管哮喘病人外周血程序性死亡因子-1及其配体的表达. 安徽医药, 2022, 26(10): 2005-2009.
18. 蔡传旭, 刘晓清, 胡海圣, 等. 过敏性疾病患者外周血可溶性PD-L1的表达及意义. 实用医学杂志, 2018, 34(18): 3036-3040.
19. Bratke K, Fritz L, Nokodian F, et al. Differential regulation of PD-1 and its ligands in allergic asthma. Clin Exp Allergy, 2017, 47(11): 1417-1425.
20. McAlees JW, Lajoie S, Dienger K, et al. Differential control of CD4+ T cell subsets by the PD-1/PD-L1 axis in allergic asthma. Eur J Immunol, 2015, 45(4): 1019-1029.
21. Wang SH, Zissler UM, Buettner M, et al. An exhausted phenotype of TH2 cells is primed by allergen exposure, but not reinforced by allergen-specific immunotherapy. Allergy, 2021, 76(9): 2827-2839.
22. Ren YY, Dong HT, Liao JY, et al. The expression and function of programmed death-ligand 1 and related cytokines in neutrophilic asthma. Ann Transl Med, 2021, 9(23): 1727.
23. Douwes J, Gibson P, Pekkanen J, et al. Non-eosinophilic asthma: importance and possible mechanisms. Thorax, 2002, 57(7): 643-648.
24. Wang WB, Yen ML, Liu KJ, et al. Interleukin-25 mediates transcriptional control of PD-L1 via STAT3 in multipotent human mesenchymal stromal cells (hMSCs) to suppress Th17 responses. Stem Cell Reports, 2015, 5(3): 392-404.
25. Helou DG, Quach C, Fung M, et al. Human PD-1 agonist treatment alleviates neutrophilic asthma by reprogramming T cells. J Allergy Clin Immunol, 2022: S0091674922010491.
26. Chang WS, Kim JY, Kim YJ, et al. Cutting edge: programmed death-1/programmed death ligand 1 interaction regulates the induction and maintenance of invariant NKT cell anergy. J Immunol, 2008, 181(10): 6707-6710.
27. Akbari O, Stock P, Singh AK, et al. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunology, 2010, 3(1): 81-91.
28. Hammad H, Lambrecht BN. The basic immunology of asthma. Cell, 2021, 184(6): 1469-1485.
29. Helou DG, Shafiei-Jahani P, Lo R, et al. PD-1 pathway regulates ILC2 metabolism and PD-1 agonist treatment ameliorates airway hyperreactivity. Nat Commun, 2020, 11(1): 3998.
30. Dahlgren MW, Jones SW, Cautivo KM, et al. Adventitial stromal cells define group 2 innate lymphoid cell tissue niches. Immunity, 2019, 50(3): 707-722. e6.
31. Taylor S, Huang Y, Mallett G, et al. PD-1 regulates KLRG1+ group 2 innate lymphoid cells. J Exp Med, 2017, 214(6): 1663-1678.
32. Schwartz C, Khan AR, Floudas A, et al. ILC2s regulate adaptive Th2 cell functions via PD-L1 checkpoint control. J Exp Med, 2017, 214(9): 2507-2521.
33. Shen C, Hupin C, Froidure A, et al. Impaired ICOSL in human myeloid dendritic cells promotes Th2 responses in patients with allergic rhinitis and asthma. Clin Exp Allergy, 2014, 44(6): 831-841.
34. Kool M, van Nimwegen M, Willart MAM, et al. An anti-inflammatory role for plasmacytoid dendritic cells in allergic airway inflammation. J Immunol, 2009, 183(2): 1074-1082.
35. Zhang X, Lewkowich IP, Köhl G, et al. A protective role for C5a in the development of allergic asthma associated with altered levels of B7-H1 and B7-DC on plasmacytoid dendritic cells. J Immunol, 2009, 182(8): 5123-5130.
36. Wang L, Pino-Lagos K, de Vries VC, et al. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A, 2008, 105(27): 9331-9336.
37. Lin CL, Huang HM, Hsieh CL, et al. Jagged1-expressing adenovirus-infected dendritic cells induce expansion of Foxp3+ regulatory T cells and alleviate T helper type 2-mediated allergic asthma in mice. Immunology, 2019, 156(2): 199-212.
38. Girodet PO, Nguyen D, Mancini JD, et al. Alternative macrophage activation is increased in asthma. Am J Respir Cell Mol Biol, 2016, 55(4): 467-475.
39. Hamano S, Matsumoto K, Tonai K, et al. Effects of corticosteroid plus long-acting beta2-agonist on the expression of PD-L1 in double-stranded RNA-induced lung inflammation in mice. J Inflamm (Lond), 2017, 14: 2.
40. Yamazaki T, Akiba H, Iwai H, et al. Expression of programmed death 1 ligands by murine T cells and APC. J Immunol, 2002, 169(10): 5538-5545.
41. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A, 2003, 100(9): 5336-5341.
42. Roche WR, Beasley R, Williams JH, et al. Subepithelial fibrosis in the bronchi of asthmatics. Lancet, 1989, 1(8637): 520-524.
43. Mostaço-Guidolin LB, Osei ET, Ullah J, et al. Defective fibrillar collagen organization by fibroblasts contributes to airway remodeling in asthma. Am J Respir Crit Care Med, 2019, 200(4): 431-443.
44. Celada LJ, Kropski JA, Herazo-Maya JD, et al. PD-1 up-regulation on CD4+ T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production. Sci Transl Med, 2018, 10(460): eaar8356.
45. Afroj T, Mitsuhashi A, Ogino H, et al. Blockade of PD-1/PD-L1 pathway enhances the antigen-presenting capacity of fibrocytes. J Immunol, 2021, 206(6): 1204-1214.
46. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol, 2001, 2(3): 261-268.
47. Patsoukis N, Brown J, Petkova V, et al. Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal, 2012, 5(230): ra46.
48. Strazza M, Adam K, Lerrer S, et al. SHP2 targets ITK downstream of PD-1 to inhibit T cell function. Inflammation, 2021, 44(4): 1529-1539.
49. Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ. FEBS Letters, 2004, 574(1-3): 37-41.
50. Fanelli G, Romano M, Nova-Lamperti E, et al. PD-L1 signaling on human memory CD4+ T cells induces a regulatory phenotype. PLoS Biol, 2021, 19(4): e3001199.
51. Usui T, Preiss JC, Kanno Y, et al. T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med, 2006, 203(3): 755-766.
52. Constant S, Pfeiffer C, Woodard A, et al. Extent of T cell receptor ligation can determine the functional differentiation of naive CD4+ T cells. J Exp Med, 1995, 182(5): 1591-1596.
53. Amarnath S, Mangus CW, Wang JCM, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med, 2011, 3(111): 111ra120-111ra120.
54. Yang K, Shrestha S, Zeng H, et al. T cell exit from quiescence and differentiation into Th2 cells depend on raptor-mTORC1-mediated metabolic reprogramming. immunity, 2013, 39(6): 1043-1056.

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