CD4+CD25+ Regulatory T Cells Decreased CD8+IL-4+Cells in a Mouse Model of Allergic Asthma

the interplay between regulatory T cells and CD8 cells in a mouse asthma model

  • Ping Li Department of Respiratory and Critical Care Medicine, Affiliated Xiangyang Hospital of Hubei University of Medicine, Xiangyang, China
  • Ze Li Department of Respiratory and Critical Care Medicine, Affiliated Xiangyang Hospital of Hubei University of Medicine, Xiangyang, China
  • Guqin Zhang Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
  • Jiong Yang Department of Respiratory and Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
  • Junwen Chen Department of Respiratory and Critical Care Medicine, Affiliated Xiangyang Hospital of Hubei University of Medicine, Xiangyang, China
Keywords: Asthma, Interferon-gamma, Interleukin-13, IL-4 CD8 cells, Regulatory T cells


Interleukin (IL)-4-producing-CD8 (cytotoxic T cells, Tc) contribute to lung eosinophilia and airway hyper-responsiveness (AHR) to an antigen. CD4+CD25+ regulatory T cells (Tregs) attenuate airway inflammation and AHR. This study investigated whether Tregs decrease Tc2frequencies in ovalbumin (OVA)-induced asthma model of mice. Female C57BL/6 mice were sensitized with OVA intraperitoneally and challenged with OVA intranasally to induce allergic asthma model. Tregs were sorted by fluorescence activated cell sorting (FACS) and magnetic activated cell sorting (MACS) microbeads. OVA-sensitized mice were injected with Tregs or phosphate buffer saline (PBS) by tail vein ahead of the first challenge. Airway inflammation and airway hyper-responsiveness (AHR)were evaluated by histological analysis and invasive method, respectively. OVA-specific IgE and cytokine levels were detected by ELISA. Flow cytometry was used to detect the percentages of Tc1 and Tc2. Gata3 and T-bet mRNA was determined by quantitative PCR (qPCR). OVA-sensitized and challenged mice displayed typical asthma features, which included eosinophilic airway inflammation, higher levels of Th2 cytokines and AHR. Gata3 mRNA, Tc2 frequencies and OVA-specific IgE levels were significantly increased in OVA-sensitized and challenged mice. Compared to PBS treatment, Tregs decreased Tc2 frequencies, airway inflammation, Th2 cytokine levels and AHR in OVA-sensitized and challenged mice. IL-13 levels were negatively correlated with Tc1 frequencies and with IFNg levels in experimental mice. Our results demonstrated that Tregs could prevent airway inflammation and AHR by decreasing Tc2 frequencies and cytokine levels in OVA-induced asthma model of mice, supporting Tregmight be as a potent therapeutic target for alleviating airway inflammation and AHR.





1. Miyahara N, B J Swanson, K Takeda, C Taube, et al. Effector CD8+ T cells mediate inflammation and airway hyper-responsiveness. Nat Med 2004; 10(8):865-69.
2. Huber M and M Lohoff. Change of paradigm: CD8+ T cells as important helper for CD4+ T cells during asthma and autoimmune encephalomyelitis. Allergo J Int 2015; 24(1):8-15.
3. Sawicka E, A Noble, C Walker, and D M Kemeny. Tc2 cells respond to soluble antigen in the respiratory tract
and induce lung eosinophilia and bronchial hyperresponsiveness. Eur J Immunol 2004; 34(9):2599-608.
4. Visekruna A, J Ritter, T Scholz, L Campos, A Guralnik, L Poncette, et al. Tc9 cells, a new subset of CD8(+) T cells, support Th2-mediated airway inflammation. Eur J Immunol 2013; 43(3):606-18.
5. Miyahara N, K Takeda, T Kodama, A Joetham, C Taube, J W Park, et al. Contribution of antigen-primed CD8+ T cells to the development of airway hyperresponsiveness and inflammation is associated with IL-13. J Immunol 2004; 172(4):2549-2558.
6. Jia Y, K Takeda, J Han, A Joetham, R A Marcus, et al. Stepwise epigenetic and phenotypic alterations poise CD8+ T cells to mediate airway hyperresponsiveness and inflammation. J Immunol 2013; 190(8):4056-65.
7. Gelfand E W and A Dakhama. CD8+ T lymphocytes and leukotriene B4: novel interactions in the persistence and progression of asthma. J Allergy Clin Immunol 2006; 117(3):577-582.
8. Schedel M, Y Jia, S Michel, K Takeda, J Domenico, A Joetham, et al. 1,25D3 prevents CD8(+)Tc2 skewing and asthma development through VDR binding changes to the Cyp11a1 promoter. Nat Commun 2016; 7:10213.
9. Li L B, D Y Leung, M J Strand, and E Goleva. ATF2 impairs glucocorticoid receptor-mediated transactivation in human CD8+ T cells. Blood 2007; 110(5):1570-7.
10. Ohnishi H, N Miyahara, A Dakhama, K Takeda, S Mathis, B Haribabu, et al. Corticosteroids enhance CD8+ T cell-mediated airway hyperresponsiveness and allergic inflammation by upregulating leukotriene B4 receptor 1. J Allergy Clin Immunol 2008; 121(4):864-71.
11. Thorburn A N and P M Hansbro. Harnessing regulatory T cells to suppress asthma: from potential to therapy. Am J Respir Cell Mol Biol 2010; 43(5):511-9.
12. Antonioli L, P Pacher, E S Vizi, and G Hasko. CD39 and CD73 in immunity and inflammation. Trends Mol Med 2013; 19(6):355-67.
13. Bastid J, A Cottalorda-Regairaz, G Alberici, N Bonnefoy, J F Eliaou, and A Bensussan. ENTPD1/CD39 is a promising therapeutic target in oncology. Oncogene 2013; 32(14):1743-51.
14. Wang L H, Y H Lin, J Yang, and W Guo. Insufficient increment of CD4+CD25+ regulatory T cells after stimulation in vitro with allergen in allergic asthma. Int Arch Allergy Immunol 2009; 148(3):199-210.
15. Li P, Y Gao, J Cao, W Wang, Y Chen, G Zhang, et al. CD39+ regulatory T cells attenuate allergic airway inflammation. Clin Exp Allergy 2015; 45(6):1126-37.
16. Baraldo S, G Turato, M G Cosio, and M Saetta. Which CD8+ T-cells in asthma? Attacking or defending? Eur Respir J 2016; 48(2):287-90.
17. Li P, J Cao, Y Chen, W Wang, and J Yang. Apyrase protects against allergic airway inflammation by decreasing the chemotactic migration of dendritic cells in mice. Int J Mol Med 2014; 34(1):269-75.
18. Idzko M, H Hammad, M van Nimwegen, M Kool, M A Willart, F Muskens, et al. Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells. Nat Med 2007; 13(8):913-9.
19. Cheng B H, T Y Hu, L H Mo, L Ma, W H Hu, Y S Li, et al. Yan-Hou-Qing formula attenuates allergic airway inflammation via up-regulation of Treg and suppressing Th2 responses in Ovalbumin-induced asthmatic mice. J Ethnopharmacol 2018; 231:275-282.
20. Takeda M, M Tanabe, W Ito, S Ueki, Y Konnno, M Chihara, et al. Gender difference in allergic airway remodelling and immunoglobulin production in mouse model of asthma. Respirology 2013; 18(5):797-806.
21. Zhang G, H Nie, J Yang, X Ding, Y Huang, H Yu, et al. Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma. Am J Physiol Lung Cell Mol Physiol 2011; 301(6):L975-984.
22. Sundrud M S and M A Nolan. Synergistic and combinatorial control of T cell activation and differentiation by transcription factors. Curr Opin Immunol 2010; 22(3):286-92.
23. Amsen D, C G Spilianakis, and R A Flavell. How are T(H)1 and T(H)2 effector cells made? Curr Opin Immunol 2009; 21(2):153-60.
24. Ravensberg A J, A M Slats, S van Wetering, K Janssen, S van Wijngaarden, R de Jeu, et al. CD8(+) T cells characterize early smoking-related airway pathology in patients with asthma. Respir Med, 2013; 107(7):959-66.
25. van Rensen E L, J K Sont, C E Evertse, L N Willems, T Mauad, P S Hiemstra, et al. Bronchial CD8 cell infiltrate and lung function decline in asthma. Am J Respir Crit Care Med 2005; 172(7):837-41.
26. Chung E H, Y Jia, H Ohnishi, K Takeda, D Y Leung, E R Sutherland, et al. Leukotriene B4 receptor 1 is differentially expressed on peripheral T cells of steroid-sensitive and -resistant asthmatics. Ann Allergy Asthma Immunol 2014; 112(3):211-6.
27. Hamelmann E, A Oshiba, J Paluh, K Bradley, J Loader, T A Potter, et al. Requirement for CD8+ T cells in the development of airway hyperresponsiveness in a marine model of airway sensitization. J Exp Med 1996; 183(4):1719-29.
28. den Otter I, L N Willems, A van Schadewijk, S van Wijngaarden, K Janssen, R C de Jeu, et al. Lung function decline in asthma patients with elevated bronchial CD8, CD4 and CD3 cells. Eur Respir J 2016; 48(2):393-402
29. Dakhama A, M L Collins, H Ohnishi, E Goleva, D Y Leung, R Alam, et al. IL-13-producing BLT1-positive CD8 cells are increased in asthma and are associated with airway obstruction. Allergy 2013; 68(5):666-73.
30. Koya T, N Miyahara, K Takeda, S Matsubara, H Matsuda, C Swasey, et al. CD8+ T cell-mediated airway hyperresponsiveness and inflammation is dependent on CD4+IL-4+ T cells. J Immunol 2007; 179(5):278796.
31. Harris D P, S Goodrich, K Mohrs, M Mohrs, and F E Lund. Cutting edge: the development of IL-4-producing B cells (B effector 2 cells) is controlled by IL-4, IL-4 receptor alpha, and Th2 cells. J Immunol 2005; 175(11):7103-7.
32. Akbari O, P Stock, E Meyer, M Kronenberg, S Sidobre, T Nakayama, et al. Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 2003; 9(5):582-8.
33. Barlow J L, A Bellosi, C S Hardman, L F Drynan, S H Wong, J P Cruickshank, et al. Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity. J Allergy Clin Immunol 2012; 129(1):191-8.
34. Tang Y, S P Guan, B Y Chua, Q Zhou, A W Ho, et al. Antigen-specific effector CD8 T cells regulate allergic responses via IFN-gamma and dendritic cell function. J Allergy Clin Immunol 2012; 129(6):1611-20.
35. Chen D, Y Wang, H Wang, Y Wu, S Xia, and M Zhang. CD8(+) T activation attenuates CD4(+) T proliferation through dendritic cells modification. Cell Immunol 2015; 296(2):138-48.
36. Ling E M, T Smith, X D Nguyen, C Pridgeon, M Dallman, J Arbery, et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 2004; 363(9409):608-15.
37. Albano G D, C Di Sano, A Bonanno, L Riccobono, R Gagliardo, P Chanez, et al. Th17 immunity in children with allergic asthma and rhinitis: a pharmacological approach. PLoS One 2013; 8(4):e58892.
How to Cite
Li P, Li Z, Zhang G, Yang J, Chen J. CD4+CD25+ Regulatory T Cells Decreased CD8+IL-4+Cells in a Mouse Model of Allergic Asthma. Iran J Allergy Asthma Immunol. 18(4):369-378.
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