PD-1/PD-L1軸在慢性阻塞性肺疾病中的研究進展_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

翟麗穎 , 叢金鵬 , 糜麗云 ,  鞏海紅 ,  于文成

青島大學附屬醫院呼吸與危重癥醫學科（山東青島 266003）;

Corresponding?author：

鞏海紅, Email: qiqoqqq@163.com; 于文成, Email: qdyuwencheng@163.com

Keywords：

DOI：

10.7507/1671-6205.202211038

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Citation： 翟麗穎, 叢金鵬, 糜麗云, 鞏海紅, 于文成. PD-1/PD-L1軸在慢性阻塞性肺疾病中的研究進展. Chinese Journal of Respiratory and Critical Care Medicine, 2024, 23(1): 69-75. doi: 10.7507/1671-6205.202211038 Copy

1.	Viegi G, Maio S, Fasola S, et al. Global burden of chronic respiratory diseases. J Aerosol Med Pulm Drug Deliv, 2020, 33(4): 171-177.
2.	Aghapour M, Raee P, Moghaddam SJ, et al. Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: role of cigarette smoke exposure. Am J Respir Cell Mol Biol, 2018, 58(2): 157-169.
3.	Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J, 1992, 11(11): 3887-3895.
4.	Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity, 2004, 20(3): 337-347.
5.	Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 1996, 8(5): 765-772.
6.	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.
7.	Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
8.	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.
9.	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.
10.	Dong HD, Zhu GF, 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.	Lin DY, Tanaka Y, Iwasaki M, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A, 2008, 105(8): 3011-3016.
12.	Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
13.	Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity, 2018, 48(3): 434-452.
14.	Krogsgaard M, Huppa JB, Purbhoo MA, et al. Linking molecular and cellular events in T-cell activation and synapse formation. Semin Immunol, 2003, 15(6): 307-315.
15.	Lee GR. The Balance of Th17 versus Treg Cells in Autoimmunity. Int J Mol Sci, 2018, 19(3).
16.	Esensten JH, Helou YA, Chopra G, et al. CD28 Costimulation: From Mechanism to Therapy. Immunity, 2016, 44(5): 973-988.
17.	Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 2012, 209(6): 1201-1217.
18.	Wang Q, Bardhan K, Boussiotis VA, et al. The PD-1 Interactome. Adv Biol (Weinh), 2021, 5(9): e2100758.
19.	Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004, 574(1-3): 37-41.
20.	Carter L, Fouser LA, Jussif J, et al. PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol, 2002, 32(3): 634-643.
21.	Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A, 2013, 110(27): E2480-2489.
22.	Cosio MG, Majo J, Cosio MG. Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest, 2002, 121(5 Suppl): 160s-165s.
23.	Williams M, Todd I, Fairclough LC. The role of CD8 + T lymphocytes in chronic obstructive pulmonary disease: a systematic review. Inflamm Res, 2021, 70(1): 11-18.
24.	Zhuang H, Li N, Chen SD, et al. Correlation between level of autophagy and frequency of CD8⁺ T cells in patients with chronic obstructive pulmonary disease. J Int Med Res, 2020, 48(9): 300060520952638.
25.	Motz GT, Eppert BL, Sun GY, et al. Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol, 2008, 181(11): 8036-8043.
26.	Saetta M, Di Stefano A, Turato G, et al. CD8⁺ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1998, 157(3 Pt 1): 822-826.
27.	Roos-Engstrand E, Ekstrand-Hammarstr?m B, Pourazar J, et al. Influence of smoking cessation on airway T lymphocyte subsets in COPD. COPD, 2009, 6(2): 112-120.
28.	Zhu J, Mallia P, Footitt J, et al. Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD. J Allergy Clin Immunol, 2020, 146(4): 840-850. e847.
29.	Kojima H, Shinohara N, Hanaoka S, et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity, 1994, 1(5): 357-364.
30.	Maeno T, Houghton AM, Quintero PA, et al. CD8⁺ T Cells are required for inflammation and destruction in cigarette smoke-induced emphysema in mice. J Immunol, 2007, 178(12): 8090-8096.
31.	Paats MS, Bergen IM, Hoogsteden HC, et al. Systemic CD4⁺ and CD8⁺ T-cell cytokine profiles correlate with GOLD stage in stable COPD. Eur Respir J, 2012, 40(2): 330-337.
32.	Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J, 2001, 17(5): 946-953.
33.	O'Shaughnessy TC, Ansari TW, Barnes NC, et al. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8⁺ T lymphocytes with FEV₁. Am J Respir Crit Care Med, 1997, 155(3): 852-857.
34.	Majori M, Corradi M, Caminati A, et al. Predominant TH1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J Allergy Clin Immunol, 1999, 103(3 Pt 1): 458-462.
35.	Sun J, Liu T, Yan Y, et al. The role of Th1/Th2 cytokines played in regulation of specific CD4 (+) Th1 cell conversion and activation during inflammatory reaction of chronic obstructive pulmonary disease. Scand J Immunol, 2018, 88(1): e12674.
36.	Uzeloto JS, de Toledo-Arruda AC, Silva BSA, et al. Systemic cytokine profiles of CD4⁺ T lymphocytes correlate with clinical features and functional status in stable COPD. Int J Chron Obstruct Pulmon Dis, 2020, 15: 2931-2940.
37.	Lee SH, Goswami S, Grudo A, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med, 2007, 13(5): 567-569.
38.	Gharib SA, Manicone AM, Parks WC. Matrix metalloproteinases in emphysema. Matrix Biol, 2018, 73: 34-51.
39.	Louren?o JD, Ito JT, Martins MA, et al. Th17/Treg imbalance in chronic obstructive pulmonary disease: clinical and experimental evidence. Front Immunol, 2021, 12: 804919.
40.	Wang HY, Ying HJ, Wang S, et al. Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease. Clin Respir J, 2015, 9(3): 330-341.
41.	Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med, 2008, 359(22): 2355-2365.
42.	Fujimoto K, Yasuo M, Urushibata K, et al. Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur Respir J, 2005, 25(4): 640-646.
43.	Mercer PF, Shute JK, Bhowmik A, et al. MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir Res, 2005, 6(1): 151.
44.	Xue WL, Ma JY, Li Y, et al. Role of CD₄⁺ T and CD₈⁺ T lymphocytes-mediated cellular immunity in pathogenesis of chronic obstructive pulmonary disease. J Immunol Res, 2022, 2022: 1429213.
45.	Stoll P, Ulrich M, Bratke K, et al. Imbalance of dendritic cell co-stimulation in COPD. Respir Res, 2015, 16(1): 19.
46.	Rui C, Defu L, Lingling W, et al. Cigarette smoke or motor vehicle exhaust exposure induces PD-L1 upregulation in lung epithelial cells in COPD model rats. COPD, 2022, 19(1): 206-215.
47.	Kalathil SG, Lugade AA, Pradhan V, et al. T-regulatory cells and programmed death 1⁺ T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2014, 190(1): 40-50.
48.	McKendry RT, Spalluto CM, Burke H, et al. Dysregulation of antiviral function of CD8(+) T cells in the chronic obstructive pulmonary disease lung. Role of the PD-1-PD-L1 axis. Am J Respir Crit Care Med, 2016, 193(6): 642-651.
49.	Tan DBA, Teo TH, Setiawan AM, et al. Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade. Clin Immunol, 2018, 188: 64-66.
50.	Huang J, Yi H, Zhao C, et al. Glucagon-like peptide-1 receptor (GLP-1R) signaling ameliorates dysfunctional immunity in COPD patients. Int J Chron Obstruct Pulmon Dis, 2018, 13: 3191-3202.
51.	Ritzmann F, Borchardt K, Vella G, et al. Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD. Am J Physiol Lung Cell Mol Physiol, 2021, 320(5): L958-l968.
52.	Li L, Yan J, Ma LQ, et al. Effects of Maxingloushi decoction on immune inflammation and programmed death markers in mice with chronic obstructive pulmonary disease. World J Emerg Med, 2022, 13(1): 32-37.
53.	Wherry EJ. T cell exhaustion. Nat Immunol, 2011, 12(6): 492-499.
54.	Tang ZS, Hao YH, Zhang EJ, et al. CD28 family of receptors on T cells in chronic HBV infection: expression characteristics, clinical significance and correlations with PD-1 blockade. Mol Med Rep, 2016, 14(2): 1107-1116.
55.	Tóth I, Le AQ, Hartjen P, et al. Decreased frequency of CD73⁺CD8⁺ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol, 2013, 94(4): 551-561.
56.	Dolina JS, Van Braeckel-Budimir N, Thomas GD, et al. CD8(+) T cell exhaustion in cancer. Front Immunol, 2021, 12: 715234.
57.	Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006, 439(7077): 682-687.
58.	Fernandes JR, Pinto TNC, Arruda LB, et al. Age-associated phenotypic imbalance in TCD4 and TCD8 cell subsets: comparison between healthy aged, smokers, COPD patients and young adults. Immun Ageing, 2022, 19(1): 9.
59.	Song DL, Yan FR, Fu HR, et al. A cellular census of human peripheral immune cells identifies novel cell states in lung diseases. Clin Transl Med, 2021, 11(11): e579.
60.	Erickson JJ, Rogers MC, Hastings AK, et al. Programmed death-1 impairs secondary effector lung CD8⁺ T cells during respiratory virus reinfection. J Immunol, 2014, 193(10): 5108-5117.
61.	Erickson JJ, Gilchuk P, Hastings AK, et al. Viral acute lower respiratory infections impair CD8⁺ T cells through PD-1. J Clin Invest, 2012, 122(8): 2967-2982.
62.	Gaber T, Strehl C, Buttgereit F. Metabolic regulation of inflammation. Nat Rev Rheumatol, 2017, 13(5): 267-279.
63.	Agarwal AR, Kadam S, Brahme A, et al. Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD). Respir Res, 2019, 20(1): 171.
64.	O'Beirne SL, Kikkers SA, Oromendia C, et al. Alveolar macrophage immunometabolism and lung function impairment in smoking and chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2020, 201(6): 735-739.
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1. Viegi G, Maio S, Fasola S, et al. Global burden of chronic respiratory diseases. J Aerosol Med Pulm Drug Deliv, 2020, 33(4): 171-177.
2. Aghapour M, Raee P, Moghaddam SJ, et al. Airway epithelial barrier dysfunction in chronic obstructive pulmonary disease: role of cigarette smoke exposure. Am J Respir Cell Mol Biol, 2018, 58(2): 157-169.
3. Ishida Y, Agata Y, Shibahara K, et al. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. Embo J, 1992, 11(11): 3887-3895.
4. Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity, 2004, 20(3): 337-347.
5. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol, 1996, 8(5): 765-772.
6. 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.
7. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med, 2016, 375(18): 1767-1778.
8. 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.
9. 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.
10. Dong HD, Zhu GF, 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. Lin DY, Tanaka Y, Iwasaki M, et al. The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proc Natl Acad Sci U S A, 2008, 105(8): 3011-3016.
12. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 2008, 26: 677-704.
13. Sun C, Mezzadra R, Schumacher TN. Regulation and Function of the PD-L1 Checkpoint. Immunity, 2018, 48(3): 434-452.
14. Krogsgaard M, Huppa JB, Purbhoo MA, et al. Linking molecular and cellular events in T-cell activation and synapse formation. Semin Immunol, 2003, 15(6): 307-315.
15. Lee GR. The Balance of Th17 versus Treg Cells in Autoimmunity. Int J Mol Sci, 2018, 19(3).
16. Esensten JH, Helou YA, Chopra G, et al. CD28 Costimulation: From Mechanism to Therapy. Immunity, 2016, 44(5): 973-988.
17. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med, 2012, 209(6): 1201-1217.
18. Wang Q, Bardhan K, Boussiotis VA, et al. The PD-1 Interactome. Adv Biol (Weinh), 2021, 5(9): e2100758.
19. Sheppard KA, Fitz LJ, Lee JM, et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett, 2004, 574(1-3): 37-41.
20. Carter L, Fouser LA, Jussif J, et al. PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol, 2002, 32(3): 634-643.
21. Wei F, Zhong S, Ma Z, et al. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A, 2013, 110(27): E2480-2489.
22. Cosio MG, Majo J, Cosio MG. Inflammation of the airways and lung parenchyma in COPD: role of T cells. Chest, 2002, 121(5 Suppl): 160s-165s.
23. Williams M, Todd I, Fairclough LC. The role of CD8 + T lymphocytes in chronic obstructive pulmonary disease: a systematic review. Inflamm Res, 2021, 70(1): 11-18.
24. Zhuang H, Li N, Chen SD, et al. Correlation between level of autophagy and frequency of CD8⁺ T cells in patients with chronic obstructive pulmonary disease. J Int Med Res, 2020, 48(9): 300060520952638.
25. Motz GT, Eppert BL, Sun GY, et al. Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol, 2008, 181(11): 8036-8043.
26. Saetta M, Di Stefano A, Turato G, et al. CD8⁺ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 1998, 157(3 Pt 1): 822-826.
27. Roos-Engstrand E, Ekstrand-Hammarstr?m B, Pourazar J, et al. Influence of smoking cessation on airway T lymphocyte subsets in COPD. COPD, 2009, 6(2): 112-120.
28. Zhu J, Mallia P, Footitt J, et al. Bronchial mucosal inflammation and illness severity in response to experimental rhinovirus infection in COPD. J Allergy Clin Immunol, 2020, 146(4): 840-850. e847.
29. Kojima H, Shinohara N, Hanaoka S, et al. Two distinct pathways of specific killing revealed by perforin mutant cytotoxic T lymphocytes. Immunity, 1994, 1(5): 357-364.
30. Maeno T, Houghton AM, Quintero PA, et al. CD8⁺ T Cells are required for inflammation and destruction in cigarette smoke-induced emphysema in mice. J Immunol, 2007, 178(12): 8090-8096.
31. Paats MS, Bergen IM, Hoogsteden HC, et al. Systemic CD4⁺ and CD8⁺ T-cell cytokine profiles correlate with GOLD stage in stable COPD. Eur Respir J, 2012, 40(2): 330-337.
32. Majo J, Ghezzo H, Cosio MG. Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema. Eur Respir J, 2001, 17(5): 946-953.
33. O'Shaughnessy TC, Ansari TW, Barnes NC, et al. Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8⁺ T lymphocytes with FEV₁. Am J Respir Crit Care Med, 1997, 155(3): 852-857.
34. Majori M, Corradi M, Caminati A, et al. Predominant TH1 cytokine pattern in peripheral blood from subjects with chronic obstructive pulmonary disease. J Allergy Clin Immunol, 1999, 103(3 Pt 1): 458-462.
35. Sun J, Liu T, Yan Y, et al. The role of Th1/Th2 cytokines played in regulation of specific CD4 (+) Th1 cell conversion and activation during inflammatory reaction of chronic obstructive pulmonary disease. Scand J Immunol, 2018, 88(1): e12674.
36. Uzeloto JS, de Toledo-Arruda AC, Silva BSA, et al. Systemic cytokine profiles of CD4⁺ T lymphocytes correlate with clinical features and functional status in stable COPD. Int J Chron Obstruct Pulmon Dis, 2020, 15: 2931-2940.
37. Lee SH, Goswami S, Grudo A, et al. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med, 2007, 13(5): 567-569.
38. Gharib SA, Manicone AM, Parks WC. Matrix metalloproteinases in emphysema. Matrix Biol, 2018, 73: 34-51.
39. Louren?o JD, Ito JT, Martins MA, et al. Th17/Treg imbalance in chronic obstructive pulmonary disease: clinical and experimental evidence. Front Immunol, 2021, 12: 804919.
40. Wang HY, Ying HJ, Wang S, et al. Imbalance of peripheral blood Th17 and Treg responses in patients with chronic obstructive pulmonary disease. Clin Respir J, 2015, 9(3): 330-341.
41. Sethi S, Murphy TF. Infection in the pathogenesis and course of chronic obstructive pulmonary disease. N Engl J Med, 2008, 359(22): 2355-2365.
42. Fujimoto K, Yasuo M, Urushibata K, et al. Airway inflammation during stable and acutely exacerbated chronic obstructive pulmonary disease. Eur Respir J, 2005, 25(4): 640-646.
43. Mercer PF, Shute JK, Bhowmik A, et al. MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation. Respir Res, 2005, 6(1): 151.
44. Xue WL, Ma JY, Li Y, et al. Role of CD₄⁺ T and CD₈⁺ T lymphocytes-mediated cellular immunity in pathogenesis of chronic obstructive pulmonary disease. J Immunol Res, 2022, 2022: 1429213.
45. Stoll P, Ulrich M, Bratke K, et al. Imbalance of dendritic cell co-stimulation in COPD. Respir Res, 2015, 16(1): 19.
46. Rui C, Defu L, Lingling W, et al. Cigarette smoke or motor vehicle exhaust exposure induces PD-L1 upregulation in lung epithelial cells in COPD model rats. COPD, 2022, 19(1): 206-215.
47. Kalathil SG, Lugade AA, Pradhan V, et al. T-regulatory cells and programmed death 1⁺ T cells contribute to effector T-cell dysfunction in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2014, 190(1): 40-50.
48. McKendry RT, Spalluto CM, Burke H, et al. Dysregulation of antiviral function of CD8(+) T cells in the chronic obstructive pulmonary disease lung. Role of the PD-1-PD-L1 axis. Am J Respir Crit Care Med, 2016, 193(6): 642-651.
49. Tan DBA, Teo TH, Setiawan AM, et al. Impaired Th1 responses in patients with acute exacerbations of COPD are improved with PD-1 blockade. Clin Immunol, 2018, 188: 64-66.
50. Huang J, Yi H, Zhao C, et al. Glucagon-like peptide-1 receptor (GLP-1R) signaling ameliorates dysfunctional immunity in COPD patients. Int J Chron Obstruct Pulmon Dis, 2018, 13: 3191-3202.
51. Ritzmann F, Borchardt K, Vella G, et al. Blockade of PD-1 decreases neutrophilic inflammation and lung damage in experimental COPD. Am J Physiol Lung Cell Mol Physiol, 2021, 320(5): L958-l968.
52. Li L, Yan J, Ma LQ, et al. Effects of Maxingloushi decoction on immune inflammation and programmed death markers in mice with chronic obstructive pulmonary disease. World J Emerg Med, 2022, 13(1): 32-37.
53. Wherry EJ. T cell exhaustion. Nat Immunol, 2011, 12(6): 492-499.
54. Tang ZS, Hao YH, Zhang EJ, et al. CD28 family of receptors on T cells in chronic HBV infection: expression characteristics, clinical significance and correlations with PD-1 blockade. Mol Med Rep, 2016, 14(2): 1107-1116.
55. Tóth I, Le AQ, Hartjen P, et al. Decreased frequency of CD73⁺CD8⁺ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion. J Leukoc Biol, 2013, 94(4): 551-561.
56. Dolina JS, Van Braeckel-Budimir N, Thomas GD, et al. CD8(+) T cell exhaustion in cancer. Front Immunol, 2021, 12: 715234.
57. Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature, 2006, 439(7077): 682-687.
58. Fernandes JR, Pinto TNC, Arruda LB, et al. Age-associated phenotypic imbalance in TCD4 and TCD8 cell subsets: comparison between healthy aged, smokers, COPD patients and young adults. Immun Ageing, 2022, 19(1): 9.
59. Song DL, Yan FR, Fu HR, et al. A cellular census of human peripheral immune cells identifies novel cell states in lung diseases. Clin Transl Med, 2021, 11(11): e579.
60. Erickson JJ, Rogers MC, Hastings AK, et al. Programmed death-1 impairs secondary effector lung CD8⁺ T cells during respiratory virus reinfection. J Immunol, 2014, 193(10): 5108-5117.
61. Erickson JJ, Gilchuk P, Hastings AK, et al. Viral acute lower respiratory infections impair CD8⁺ T cells through PD-1. J Clin Invest, 2012, 122(8): 2967-2982.
62. Gaber T, Strehl C, Buttgereit F. Metabolic regulation of inflammation. Nat Rev Rheumatol, 2017, 13(5): 267-279.
63. Agarwal AR, Kadam S, Brahme A, et al. Systemic Immuno-metabolic alterations in chronic obstructive pulmonary disease (COPD). Respir Res, 2019, 20(1): 171.
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