Inflammation Research

, Volume 68, Issue 11, pp 957–968 | Cite as

Rapamycin attenuates Tc1 and Tc17 cell responses in cigarette smoke-induced emphysema in mice

  • Hui Zhang
  • Xiu Zhou
  • Xin Chen
  • Yuanzhen Lin
  • Shilin Qiu
  • Yun Zhao
  • Qiya Tang
  • Yi Liang
  • Xiaoning ZhongEmail author
Original Research Paper


Objective and design

Chronic exposure to cigarette smoke promotes airway inflammation and emphysema accompanied by enhanced CD8+ interferon (IFN)-γ+ T(Tc1) and CD8+ interleukin (IL)-17+ T(Tc17) cell responses. The mammalian target of rapamycin (mTOR) has been involved in the pathogenesis of emphysema. Inhibiting mTOR by rapamycin has been reported to alleviate emphysema, but the mechanism is not fully understood. We aimed to explore the effect of rapamycin on Tc1 and Tc17 cell responses induced by cigarette smoke exposure.


Male C57BL/6 mice were exposed to cigarette smoke or room air for 24 weeks. Half of the smoke-exposed mice received rapamycin in the last 12 weeks. The severity of emphysema in those mice was evaluated by mean linear intercept (MLI), mean alveolar airspace area (MAA) and destructive index (DI). Bronchoalveolar lavage was collected and analyzed. Phosphorylated (p-) mTOR in CD8+ T cells, Tc1 and Tc17 cells were detected by flow cytometry. The relative expression of p-mTOR in lungs was determined by western blot analysis. IFN-γ and IL-17A levels were detected by enzyme-linked immunosorbent assays. IFN-γ, mTOR and RAR-related orphan receptor (ROR)γt mRNA levels were evaluated by the real-time polymerase chain reaction.


Elevated p-mTOR expression in CD8+ T cells and lung tissue was accompanied by the enhanced Tc1 and Tc17 cell responses in lungs of mice exposed to cigarette smoke. Rapamycin reduced inflammatory cells in BALF and decreased MLI, DI and MAA in lungs. Rapamycin decreased p-mTOR expression, and down-regulation of mTOR and RORγt mRNA levels along with the attenuation of Tc1 and Tc17 cell responses in mice with emphysema.


The mTOR was activated in CD8+ T cells accompanied by the enhanced Tc1 and Tc17 cell responses in cigarette smoke-related pulmonary inflammation. Rapamycin ameliorated emphysema and attenuated Tc1 and Tc17 cell responses probably caused by inhibiting mTOR in cigarette smoke-exposed mice.


Rapamycin Cigarette smoke CD8+IFN-γ+ T cells CD8+IL-17+ T cells Chronic obstructive pulmonary disease Emphysema 



This study was funded by grants from the National Natural Science Foundation of China (Grant numbers 81770041 and 81800037).

Compliance with ethical standards

Conflict of interest

No conflicts of interest, financial or otherwise, are declared by the author(s).


  1. 1.
    Soriano JB, Abajobir AA, Abate KH, Abera SF, Agrawal A, Ahmed MB, et al. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5:691–706.Google Scholar
  2. 2.
    Zuo L, He F, Sergakis GG, Koozehchian MS, Stimpfl JN, Rong Y, et al. Interrelated role of cigarette smoking, oxidative stress, and immune response in COPD and corresponding treatments. Am J Physiol Lung Cell Mol Physiol. 2014;307:L205–18.Google Scholar
  3. 3.
    Strzelak A, Ratajczak A, Adamiec A, Feleszko W. Tobacco smoke induces and alters immune responses in the lung triggering inflammation, allergy, asthma and other lung diseases: a mechanistic review. Int J Environ Res Public Health. 2018;15:1–35.Google Scholar
  4. 4.
    Duan MC, Zhang JQ, Liang Y, Liu GN, Xiao J, Tang HJ, et al. Infiltration of IL-17-Producing T cells and treg cells in a mouse model of smoke-induced emphysema. Inflammation. 2016;39:1334–44.Google Scholar
  5. 5.
    Qiu SL, Duan MC, Liang Y, Tang HJ, Liu GN, Zhang LM, et al. Cigarette smoke induction of interleukin-27/WSX-1 regulates the differentiation of Th1 and Th17 cells in a smoking mouse model of emphysema. Front Immunol. 2016;7:553.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Chen G, Zhou M, Chen L, Meng ZJ, Xiong XZ, Liu HJ, et al. Cigarette smoke disturbs the survival of CD8+ Tc/Tregs partially through muscarinic receptors-dependent mechanisms in chronic obstructive pulmonary disease. PLoS One. 2016;11:e0147232.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Duan MC, Huang Y, Zhong XN, Tang HJ. Th17 cell enhances CD8 T-cell cytotoxicity via IL-21 production in emphysema mice. Mediat Inflamm. 2012;2012:898053.Google Scholar
  8. 8.
    Yu MQ, Liu XS, Wang JM, Xu YJ. CD8+ Tc-lymphocytes immunodeviation in peripheral blood and airway from patients of chronic obstructive pulmonary disease and changes after short-term smoking cessation. Chin Med J. 2013;126:3608–15.Google Scholar
  9. 9.
    Liang Y, Shen Y, Kuang L, Zhou G, Zhang L, Zhong X, et al. Cigarette smoke exposure promotes differentiation of CD4+ T cells toward Th17 cells by CD40-CD40L costimulatory pathway in mice. Int J Chronic Obstr Pulm Dis. 2018;13:959–68.Google Scholar
  10. 10.
    Ni L, Dong C. Roles of myeloid and lymphoid cells in the pathogenesis of chronic obstructive pulmonary disease. Front Immunol. 2018;9:1431.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Duan MC, Tang HJ, Zhong XN, Huang Y. Persistence of Th17/Tc17 cell expression upon smoking cessation in mice with cigarette smoke-induced emphysema. Clin Dev Immunol. 2013;2013:350727.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Kuang LJ, Deng TT, Wang Q, Qiu SL, Liang Y, He ZY, et al. Dendritic cells induce Tc1 cell differentiation via the CD40/CD40L pathway in mice after exposure to cigarette smoke. Am J Physiol Lung Cell Mol Physiol. 2016;311:L581–9.Google Scholar
  13. 13.
    Qiu SL, Kuang LJ, Tang QY, Duan MC, Bai J, He ZY, et al. Enhanced activation of circulating plasmacytoid dendritic cells in patients with chronic obstructive pulmonary disease and experimental smoking-induced emphysema. Clin Immunol (Orlando, Fla). 2018;195:107–18.Google Scholar
  14. 14.
    Zhou H, Hua W, Jin Y, Zhang C, Che L, Xia L, et al. Tc17 cells are associated with cigarette smoke-induced lung inflammation and emphysema. Respirology (Carlton, Vic). 2015;20:426–33.Google Scholar
  15. 15.
    Barnes PJ. Senescence in COPD and its comorbidities. Annu Rev Physiol. 2017;79:517–39.Google Scholar
  16. 16.
    Mitani A, Ito K, Vuppusetty C, Barnes PJ, Mercado N. Restoration of corticosteroid sensitivity in chronic obstructive pulmonary disease by inhibition of mammalian target of rapamycin. Am J Respir Crit Care Med. 2016;193:143–53.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Houssaini A, Breau M, Kebe K, Abid S, Marcos E, Lipskaia L, et al. mTOR pathway activation drives lung cell senescence and emphysema. JCI Insight 2018;3:1–20.Google Scholar
  18. 18.
    Ruwanpura SM, McLeod L, Dousha LF, Seow HJ, Alhayyani S, Tate MD, et al. Therapeutic targeting of the IL-6 trans-signaling/mechanistic target of rapamycin complex 1 axis in pulmonary emphysema. Am J Respir Crit Care Med. 2016;194:1494–505.Google Scholar
  19. 19.
    Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, et al. mTORC1 and mTORC2 selectively regulate CD8+T cell differentiation. J Clin Investig. 2015;125:2090–108.Google Scholar
  21. 21.
    Feng X, Lin Z, Sun W, Hollinger MK, Desierto MJ, Keyvanfar K, et al. Rapamycin is highly effective in murine models of immune-mediated bone marrow failure. Haematologica. 2017;102:1691–703.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kato H, Perl A. Blockade of Treg Cell differentiation and function by the interleukin-21-mechanistic target of rapamycin axis via suppression of autophagy in patients with systemic lupus erythematosus. Arthritis Rheumatol (Hoboken, NJ). 2018;70:427–38.Google Scholar
  23. 23.
    Bremer SCB, Reinhardt L, Sobotta M, Hasselluhn MC, Lorf T, Ellenrieder V, et al. Pantoprazole does not affect serum trough levels of tacrolimus and everolimus in liver transplant recipients. Front Med. 2018;5:320.Google Scholar
  24. 24.
    Wang H, Li J, Han Q, Yang F, Xiao Y, Xiao M, et al. IL-12 influence mTOR to modulate CD8+ T cells differentiation through T-bet and eomesodermin in response to invasive pulmonary aspergillosis. Int J Med Sci. 2017;14:977–83.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Cui N, Wang H, Su LX, Zhang JH, Long Y, Liu DW. Role of triggering receptor expressed on myeloid cell-1 expression in mammalian target of rapamycin modulation of CD8+ T-cell differentiation during the immune response to invasive pulmonary aspergillosis. Chin Med J. 2017;130:1211–7.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Saleiro D, Platanias LC. Intersection of mTOR and STAT signaling in immunity. Trends Immunol. 2015;36:21–9.Google Scholar
  27. 27.
    Jung U, Foley JE, Erdmann AA, Toda Y, Borenstein T, Mariotti J, et al. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant. 2006;12:905–18.Google Scholar
  28. 28.
    Ren W, Yin J, Duan J, Liu G, Tan B, Yang G, et al. mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets. Eur J Immunol. 2016;46:291–9.Google Scholar
  29. 29.
    Avila CL, Zimmerer JM, Elzein SM, Pham TA, Abdel-Rasoul M, Bumgardner GL. mTOR inhibition suppresses posttransplant alloantibody production through direct inhibition of alloprimed B cells and sparing of CD8+ antibody-suppressing T cells. Transplantation. 2016;100:1898–906.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Bai J, Qiu SL, Zhong XN, Huang QP, He ZY, Zhang JQ, et al. Erythromycin enhances CD4+Foxp3+ regulatory T-cell responses in a rat model of smoke-induced lung inflammation. Mediat Inflamm. 2012;2012:410232.Google Scholar
  31. 31.
    Eidelman DH, Ghezzo H, Kim WD, Cosio MG. The destructive index and early lung destruction in smokers. Am Rev Respir Dis. 1991;144:156.Google Scholar
  32. 32.
    Goldstein I, Bughalo M, Marquette C, Lenaour G, Lu Q, Rouby J. Mechanical ventilation-induced air-space enlargement during experimental pneumonia in piglets. Am J Respir Crit Care Med. 2001;163:958.Google Scholar
  33. 33.
    Lee B, Ko E, Lee J, Jo Y, Hwang H, Goh TS, et al. Soluble common gamma chain exacerbates COPD progress through the regulation of inflammatory T cell response in mice. Int J Chronic Obstr Pulm Dis. 2017;12:817–27.Google Scholar
  34. 34.
    Chen L, Chen G, Zhang MQ, Xiong XZ, Liu HJ, Xin JB, et al. Imbalance between subsets of CD8+ peripheral blood T cells in patients with chronic obstructive pulmonary disease. PeerJ. 2016;4:e2301.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Xu WH, Hu XL, Liu XF, Bai P, Sun YC. Peripheral Tc17 and Tc17/interferon-gamma cells are increased and associated with lung function in patients with chronic obstructive pulmonary disease. Chin Med J. 2016;129:909–16.PubMedPubMedCentralGoogle Scholar
  36. 36.
    Dua K, Malyla V, Singhvi G, Wadhwa R, Krishna RV, Shukla SD, et al. Increasing complexity and interactions of oxidative stress in chronic respiratory diseases: an emerging need for novel drug delivery systems. Chem Biol Interact. 2018;299:168–78.Google Scholar
  37. 37.
    Hodge G, Hodge S. Steroid resistant CD8+CD28null NKT-like pro-inflammatory cytotoxic cells in chronic obstructive pulmonary disease. Front Immunol. 2016;7:617.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity. 2016;45:540–54.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity. 2010;33:301–11.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Curtis MM, Sing Sing W, Wilson CB. IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. J Immunol. 2009;183:381–7.PubMedPubMedCentralGoogle Scholar
  41. 41.
    Wang Y, Liu J, Zhou JS, Huang HQ, Li ZY, Xu XC, et al. MTOR suppresses cigarette smoke-induced epithelial cell death and airway inflammation in chronic obstructive pulmonary disease. J Immunol. (Baltimore, Md : 1950). 2018;200:2571–80.Google Scholar
  42. 42.
    Weichhart T, Hengstschlager M, Linke M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015;15:599–614.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Danner S, Sigrist S, Moreau F, Mandes K, Vodouhé C, Langlois A, et al. Influence of rapamycin on rat macrophage viability and chemotaxis toward allogenic pancreatic islet supernates. Transplant Proc. 2008;40:470–2.Google Scholar
  44. 44.
    Hackstein H. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood. 2003;101:4457–63.Google Scholar
  45. 45.
    Lorne E, Zhao X, Zmijewski JW, Liu G, Park YJ, Tsuruta Y, et al. Participation of mammalian target of rapamycin complex 1 in toll-like receptor 2- and 4-induced neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol. 2009;41:237–45.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Hu Y, Lou J, Mao YY, Lai TW, Liu LY, Zhu C, et al. Activation of MTOR in pulmonary epithelium promotes LPS-induced acute lung injury. Autophagy. 2016;12:2286–99.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Hui Zhang
    • 1
  • Xiu Zhou
    • 1
  • Xin Chen
    • 1
  • Yuanzhen Lin
    • 1
  • Shilin Qiu
    • 1
  • Yun Zhao
    • 1
  • Qiya Tang
    • 1
  • Yi Liang
    • 1
  • Xiaoning Zhong
    • 1
    Email author
  1. 1.Department of Respiratory and Critical Care MedicineThe First Affiliated Hospital of Guangxi Medical UniversityNanningChina

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