CD39/CD73 and the imbalance of Th17 cells and regulatory T cells in allergic asthma

Wang,Lin‑Lin; Tang,Hua‑Ping; Shi,Guo‑Chao; Wan,Huan‑Ying; Tang,Wei; Hou,Xiao‑Xia; Pan,Li‑Na; Shi,Bao‑Yu; Tao,Lian‑Qin

doi:10.3892/mmr.2013.1692

CD39/CD73 and the imbalance of Th17 cells and regulatory T cells in allergic asthma

Authors:
- Lin‑Lin Wang
- Hua‑Ping Tang
- Guo‑Chao Shi
- Huan‑Ying Wan
- Wei Tang
- Xiao‑Xia Hou
- Li‑Na Pan
- Bao‑Yu Shi
- Lian‑Qin Tao
View Affiliations

Affiliations: Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China, Department of Pulmonary Medicine, Qingdao Municipal Hospital, Qingdao University School of Medicine, Qingdao, Shandong 266011, P.R. China
Published online on: September 18, 2013 https://doi.org/10.3892/mmr.2013.1692
Pages: 1432-1438

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

In the immune system, CD4+CD25+Foxp3+ regulatory T cells (Tregs) maintain self‑tolerance and Th17 cells mediate inflammatory responses. CD39 is expressed on the surface of a subset of naturally occurring human Tregs that are important in constraining pathogenic Th17 cells. Additional studies have shown that Tregs differentiate into interleukin‑17 (IL‑17)+Foxp3+ T cells. Our previous study indicated an imbalance of Th17 and Tregs in allergic asthma; however, the underlying mechanisms remain poorly understood. Using quantitative PCR (qPCR), CD39 and CD73 mRNA levels in CD4+ T cells were investigated. Flow cytometry was used to analyze the proportion of IL‑17+Foxp3+ T cells, and CD39 and CD73 expressed by CD4+ T cells and Tregs in the peripheral blood of the subjects. The results of the present study demonstrated an increased frequency of CD4+Foxp3+IL‑17+ T cells in moderate to severe asthma. A deficiency in CD39 expressed on the surface of CD4+ T cells and Tregs was observed in asthma patients. The expression of CD39 and CD73 on the surface of CD4+ T cells and Tregs was negatively correlated with the number of Th17 cells. These results indicated that the plasticity of Tregs transforming to IL‑17+Foxp3+CD4+ T cells, the reduced frequency of CD39+ Tregs and less effective suppression of IL‑17 production by residual CD39+ Tregs leads to an imbalance of Th17 and Tregs in asthma. Therefore, enhanced CD39 activity is hypothesized to prevent the progression of asthma.

View Figures

View References

1	Shevach EM: CD4⁺CD25⁺ suppressor T cells: more questions than answers. Nat Rev Immunol. 2:389–400. 2002.
2	Tesmer LA, Lundy SK, Sarkar S and Fox DA: Th17 cells in human disease. Immunol Rev. 223:87–113. 2008. View Article : Google Scholar : PubMed/NCBI
3	Weaver CT, Harrington LE, Mangan PR, Gavrieli M and Murphy KM: Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity. 24:677–688. 2006. View Article : Google Scholar : PubMed/NCBI
4	Zhou L, Chong MM and Littman DR: Plasticity of CD4⁺ T cell lineage differentiation. Immunity. 30:646–655. 2009.
5	Dong C: TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 8:337–348. 2008. View Article : Google Scholar : PubMed/NCBI
6	Chen Q, Yang W, Gupta S, Biswas P, Smith P, Bhagat G and Pernis AB: IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity. 29:899–911. 2008. View Article : Google Scholar : PubMed/NCBI
7	Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ and Littman DR: The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17⁺ T helper cells. Cell. 126:1121–1133. 2006. View Article : Google Scholar : PubMed/NCBI
8	Josefowicz SZ and Rudensky A: Control of regulatory T cell lineage commitment and maintenance. Immunity. 30:616–625. 2009. View Article : Google Scholar : PubMed/NCBI
9	Lee YK, Mukasa R, Hatton RD and Weaver CT: Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol. 21:274–280. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kryczek I, Wu K, Zhao E, Wei S, Vatan L, Szeliga W, Huang E, Greenson J, Chang A, Roliński J, et al: IL-17⁺ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol. 186:4388–4395. 2011.PubMed/NCBI
11	Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I and Koenen HJ: Foxp3⁺ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 131:1853–1860. 2011.
12	Liu T, Song CH, Liu AM, Xie C, Zhao F, Chen X, Cheng L and Yang PC: Forkhead box P3⁺ T cells express interleukin-17 in nasal mucosa of patients with both allergic rhinitis and polyposis. Clin Exp Immunol. 163:59–64. 2011.
13	Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F and D’Ambrosio D: Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med. 194:847–853. 2001.PubMed/NCBI
14	Paust S, Lu L, McCarty N and Cantor H: Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease. Proc Natl Acad Sci USA. 101:10398–10403. 2004. View Article : Google Scholar : PubMed/NCBI
15	Lehmann J, Huehn J, de la Rosa M, Maszyna F, Kretschmer U, Krenn V, Brunner M, Scheffold A and Hamann A: Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25⁺ as well as CD25- regulatory T cells. Proc Natl Acad Sci USA. 99:13031–13036. 2002. View Article : Google Scholar : PubMed/NCBI
16	Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A and Bluestone JA: B7/CD28 costimulation is essential for the homeostasis of the CD4⁺CD25⁺ immunoregulatory T cells that control autoimmune diabetes. Immunity. 12:431–440. 2000. View Article : Google Scholar : PubMed/NCBI
17	Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, et al: CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4⁺ Treg cells. J Exp Med. 203:1701–1711. 2006. View Article : Google Scholar : PubMed/NCBI
18	Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al: Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 204:1257–1265. 2007. View Article : Google Scholar : PubMed/NCBI
19	Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D, Bernardi G, Dell’Acqua ML, et al: Expression of ectonucleotidase CD39 by Foxp3⁺ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 110:1225–1232. 2007. View Article : Google Scholar : PubMed/NCBI
20	Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O’Farrelly C, Tubridy N and Mills KH: CD39⁺Foxp3⁺ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol. 183:7602–7610. 2009.PubMed/NCBI
21	Huang S, Apasov S, Koshiba M and Sitkovsky M: Role of A2a extracellular adenosine receptor-mediated signaling in adenosine mediated inhibition of T-cell activation and expansion. Blood. 90:1600–1610. 1997.PubMed/NCBI
22	Boulet LP, FitzGerald JM, Levy ML, Cruz AA, Pedersen S, Haahtela T and Bateman ED: A guide to the translation of the Global Initiative for Asthma (GINA) strategy into improved care. Eur Respir J. 39:1220–1229. 2012. View Article : Google Scholar : PubMed/NCBI
23	Shi YH, Shi GC, Wan HY, Jiang LH, Ai XY, Zhu HX, Tang W, Ma JY, Jin XY and Zhang BY: Co-existence of Th1/Th2 and Th17/Treg imbalances in patients with allergic asthma and its significance. Chin Med J (Engl). 124:1951–1956. 2011.PubMed/NCBI
24	Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA and Rudensky AY: Foxp3-dependent programme of regulatory T cell differentiation. Nature. 445:771–775. 2007. View Article : Google Scholar : PubMed/NCBI
25	Flores-Borja F, Jury EC, Mauri C and Ehrenstein MR: Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci USA. 105:19396–19401. 2008. View Article : Google Scholar : PubMed/NCBI
26	Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B, Parente E, Filì L, Ferri S, Frosali F, et al: Phenotypic and functional features of human Th17 cells. J Exp Med. 204:1849–1861. 2007. View Article : Google Scholar : PubMed/NCBI