Expression of CD39 on FoxP3+ T regulatory cells correlates with progression of HBV infection

BMC Immunology

Yuzhang Wu³  Bing Ni³  Yanhua Zheng¹  Li Jiang²  Yan Tang³ 

[1] Department of Pathology and Experimental Medicine, 306 Hospital of PLA, Beijing 100101, People Republic of China;Institution of Infectious Diseases, Southwest Hospital, the Third Military Medical University of Chinese PLA, Chongqing 400038, People Republic of China;Institute of Immunology, PLA, Third Military Medical University, Chongqing 400038, People Republic of China

关键词: Regulatory T lymphocyte;    CD39;    Hepatitis B;   

Others  :  1077928
DOI  :  10.1186/1471-2172-13-17

 received in 2012-02-06, accepted in 2012-04-11,  发布年份 2012

【 摘 要 】

Background

Although it is known that regulatory T cells (Tregs) can suppress the function of effector T cells, and may contribute to impaired immune response, the precise role of Tregs during the course of hepatitis B virus (HBV) infection remains to be elucidated. A newly identified subset of the CD4⁺Foxp3⁺ Tregs, the CD39⁺ Tregs, has been associated with viral infections and autoimmune diseases. Therefore, we hypothesized that this discrete Treg subset may contribute to the chronic infection of HBV.

Results

Initial characterization studies of healthy peripheral CD39⁺FoxP3⁺CD4⁺ T cells revealed that the majority were CD45RA^- Treg cells. Subsequent analysis of HBV-infected patients (38 asymptomatic HBV carriers (AsCs), 37 chronic active hepatitis B (CAH), 29 HBV-associated acute-on-chronic liver failure (ACLF)) and healthy individuals (25 controls) was conducted to assess association with HBV copy number and the liver injury marker alanine aminotransferase (ALT). A higher percentage of CD39⁺ Tregs was detected within the population of FoxP3⁺CD4⁺ T cells in peripheral blood of AsCs patients. Moreover, the percentage of CD39⁺ Tregs was significantly less in CAH and ACLF patients. The increased proportions of circulating CD39⁺ Tregs were positively correlated with serum viral load, but inversely correlated with serum ALT level.

Conclusion

These findings not only suggest that CD39⁺ Treg cells may be involved in HBV disease progression but also identify CD39⁺ Tregs as a dynamic immune regulatory cell population that may represent a new target of immunomodulatory therapeutic interventions.

【 授权许可】

   
2012 Tang et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Chisari FV, Isogawa M, Wieland SF: Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris) 2010, 58:258-266.
• [2]Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol 2005, 5:215-229.
• [3]Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U: Natural regulatory T cells and persistent viral infection. J Virol 2008, 82:21-30.
• [4]Belkaid Y: Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 2007, 7:875-888.
• [5]Yang G, Liu A, Xie Q, Guo TB, Wan B, Zhou B, Zhang JZ: Association of CD4 + CD25 + Foxp3+ regulatory T cells with chronic activity and viral clearance in patients with hepatitis B. Int Immunol 2007, 19:133-140.
• [6]Wang Q, Zheng Y, Huang Z, Tian Y, Zhou J, Mao Q, Wu Y, Ni B: Activated IL-23/IL-17 pathway closely correlates with increased Foxp3 expression in livers of chronic hepatitis B patients. BMC Immunol 2011, 12:25. BioMed Central Full Text
• [7]Stoop JN, van der Molen RG, Baan CC, van der Laan LJ, Kuipers EJ, Kusters JG, Janssen HL: Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection. Hepatology 2005, 41:771-778.
• [8]Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, Zhao JM, Zhang B, Shi M, Ding X, et al.: Circulating and liver resident CD4 + CD25+ regulatory T cells actively influence the antiviral immune response and disease progression in patients with hepatitis B. J Immunol 2006, 177:739-747.
• [9]Franzese O, Kennedy PT, Gehring AJ, Gotto J, Williams R, Maini MK, Bertoletti A: Modulation of the CD8 + -T-cell response by CD4+ CD25+ regulatory T cells in patients with hepatitis B virus infection. J Virol 2005, 79:3322-3328.
• [10]Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T: Regulatory T cells: how do they suppress immune responses? Int Immunol 2009, 21:1105-1111.
• [11]Sakaguchi S, Miyara M, Costantino CM, Hafler DA: FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010, 10:490-500.
• [12]Camisaschi C, Casati C, Rini F, Perego M, De Filippo A, Triebel F, Parmiani G, Belli F, Rivoltini L, Castelli C: LAG-3 expression defines a subset of CD4(+)CD25(high)Foxp3(+) regulatory T cells that are expanded at tumor sites. J Immunol 2010, 184:6545-6551.
• [13]Nikolova M, Carriere M, Jenabian MA, Limou S, Younas M, Kok A, Hue S, Seddiki N, Hulin A, Delaneau O, et al.: CD39/adenosine pathway is involved in AIDS progression. PLoS Pathog 2011, 7:e1002110.
• [14]Moreno-Fernandez ME, Rueda CM, Rusie LK, Chougnet CA: Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism. Blood 2011, 117:5372-5380.
• [15]Schulze Zur Wiesch J, Thomssen A, Hartjen P, Toth I, Lehmann C, Meyer-Olson D, Colberg K, Frerk S, Babikir D, Schmiedel S, et al.: Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease. J Virol 2011, 85:1287-1297.
• [16]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 2007, 204:1257-1265.
• [17]Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner 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 2007, 110:1225-1232.
• [18]Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Lenzner DE, Jackson EK, Gorelik E, Lang S, Johnson JT, Whiteside TL: Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res 2009, 15:6348-6357.
• [19]Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, Tubridy N, Mills KH: CD39 + Foxp3 + regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009, 183:7602-7610.
• [20]Mittag D, Scholzen A, Varese N, Baxter L, Paukovics G, Harrison LC, Rolland JM, O'Hehir RE: The effector T cell response to ryegrass pollen is counterregulated by simultaneous induction of regulatory T cells. J Immunol 2010, 184:4708-4716.
• [21]Robson SC, Wu Y, Sun X, Knosalla C, Dwyer K, Enjyoji K: Ectonucleotidases of CD39 family modulate vascular inflammation and thrombosis in transplantation. Semin Thromb Hemost 2005, 31:217-233.
• [22]Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 2007, 45:(2):507-539.
• [23]Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol 1991, 13:372-374.
• [24]Ebinuma H, Nakamoto N, Li Y, Price DA, Gostick E, Levine BL, Tobias J, Kwok WW, Chang KM: Identification and in vitro expansion of functional antigen-specific CD25+ FoxP3+ regulatory T cells in hepatitis C virus infection. J Virol 2008, 82:5043-5053.
• [25]Dwyer KM, Deaglio S, Gao W, Friedman D, Strom TB, Robson SC: CD39 and control of cellular immune responses. Purinergic Signal 2007, 3:171-180.
• [26]Ndhlovu LC, Leal FE, Eccles-James IG, Jha AR, Lanteri M, Norris PJ, Barbour JD, Wachter DJ, Andersson J, Tasken K, et al.: A novel human CD4+ T-cell inducer subset with potent immunostimulatory properties. Eur J Immunol 2010, 40:134-141.
• [27]Mandapathil M, Lang S, Gorelik E, Whiteside TL: Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J Immunol Methods 2009, 346:55-63.
• [28]Dwyer KM, Hanidziar D, Putheti P, Hill PA, Pommey S, McRae JL, Winterhalter A, Doherty G, Deaglio S, Koulmanda M, et al.: Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant 2010, 10:2410-2420.
• [29]Moncrieffe H, Nistala K, Kamhieh Y, Evans J, Eddaoudi A, Eaton S, Wedderburn LR: High expression of the ectonucleotidase CD39 on T cells from the inflamed site identifies two distinct populations, one regulatory and one memory T cell population. J Immunol 2010, 185:134-143.
• [30]Alatrakchi N, Koziel M: Regulatory T cells and viral liver disease. J Viral Hepat 2009, 16:223-229.
• [31]Friedman DJ, Kunzli BM, YI AR, Sevigny J, Berberat PO, Enjyoji K, Csizmadia E, Friess H, Robson SC: From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease. Proc Natl Acad Sci USA 2009, 106:16788-16793.
• [32]Sitkovsky MV: T regulatory cells: hypoxia-adenosinergic suppression and redirection of the immune response. Trends Immunol 2009, 30:102-108.
• [33]Bynoe MS, Viret C: Foxp3 + CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism. Trends Immunol 2008, 29:99-102.
• [34]Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, Herberg J, Gilson R, Alisa A, et al.: The role of virus-specific CD8(+) cells in liver damage and viral control during persistent hepatitis B virus infection. J Exp Med 2000, 191:1269-1280.
• [35]Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, et al.: ATP drives lamina propria T(H)17 cell differentiation. Nature 2008, 455:808-812.
• [36]Salcido-Ochoa F, Tsang J, Tam P, Falk K, Rotzschke O: Regulatory T cells in transplantation: does extracellular adenosine triphosphate metabolism through CD39 play a crucial role? Transplant Rev (Orlando) 2010, 24:52-66.
• [37]Tan AT, Koh S, Goh W, Zhe HY, Gehring AJ, Lim SG, Bertoletti A: A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. J Hepatol 2010, 52:330-339.