{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:23:27Z","timestamp":1791289407052,"version":"4.3.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["BMC Immunol"],"published-print":{"date-parts":[[2012,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>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<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> Tregs, the CD39<jats:sup>+<\/jats:sup> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Initial characterization studies of healthy peripheral CD39<jats:sup>+<\/jats:sup>FoxP3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> T cells revealed that the majority were CD45RA<jats:sup>-<\/jats:sup> 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<jats:sup>+<\/jats:sup> Tregs was detected within the population of FoxP3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup> T cells in peripheral blood of AsCs patients. Moreover, the percentage of CD39<jats:sup>+<\/jats:sup> Tregs was significantly less in CAH and ACLF patients. The increased proportions of circulating CD39<jats:sup>+<\/jats:sup> Tregs were positively correlated with serum viral load, but inversely correlated with serum ALT level.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>These findings not only suggest that CD39<jats:sup>+<\/jats:sup> Treg cells may be involved in HBV disease progression but also identify CD39<jats:sup>+<\/jats:sup> Tregs as a dynamic immune regulatory cell population that may represent a new target of immunomodulatory therapeutic interventions.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2172-13-17","type":"journal-article","created":{"date-parts":[[2012,4,11]],"date-time":"2012-04-11T02:13:54Z","timestamp":1334110434000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Expression of CD39 on FoxP3+ T regulatory cells correlates with progression of HBV infection"],"prefix":"10.1186","volume":"13","author":[{"given":"Yan","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuzhang","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,4,11]]},"reference":[{"key":"439_CR1","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1016\/j.patbio.2009.11.001","volume":"58","author":"FV Chisari","year":"2010","unstructured":"Chisari FV, Isogawa M, Wieland SF: Pathogenesis of hepatitis B virus infection. Pathol Biol (Paris). 2010, 58: 258-266. 10.1016\/j.patbio.2009.11.001.","journal-title":"Pathol Biol (Paris)"},{"key":"439_CR2","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1038\/nri1573","volume":"5","author":"B Rehermann","year":"2005","unstructured":"Rehermann B, Nascimbeni M: Immunology of hepatitis B virus and hepatitis C virus infection. Nat Rev Immunol. 2005, 5: 215-229. 10.1038\/nri1573.","journal-title":"Nat Rev Immunol"},{"key":"439_CR3","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1128\/JVI.01768-07","volume":"82","author":"S Li","year":"2008","unstructured":"Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U: Natural regulatory T cells and persistent viral infection. J Virol. 2008, 82: 21-30. 10.1128\/JVI.01768-07.","journal-title":"J Virol"},{"key":"439_CR4","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/nri2189","volume":"7","author":"Y Belkaid","year":"2007","unstructured":"Belkaid Y: Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol. 2007, 7: 875-888. 10.1038\/nri2189.","journal-title":"Nat Rev Immunol"},{"key":"439_CR5","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1093\/intimm\/dxl130","volume":"19","author":"G Yang","year":"2007","unstructured":"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.","journal-title":"Int Immunol"},{"key":"439_CR6","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1186\/1471-2172-12-25","volume":"12","author":"Q Wang","year":"2011","unstructured":"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: 25-10.1186\/1471-2172-12-25.","journal-title":"BMC Immunol"},{"key":"439_CR7","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1002\/hep.20649","volume":"41","author":"JN Stoop","year":"2005","unstructured":"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. 10.1002\/hep.20649.","journal-title":"Hepatology"},{"key":"439_CR8","doi-asserted-by":"publisher","first-page":"739","DOI":"10.4049\/jimmunol.177.1.739","volume":"177","author":"D Xu","year":"2006","unstructured":"Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, Zhao JM, Zhang B, Shi M, Ding X: 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.","journal-title":"J Immunol"},{"key":"439_CR9","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1128\/JVI.79.6.3322-3328.2005","volume":"79","author":"O Franzese","year":"2005","unstructured":"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. 10.1128\/JVI.79.6.3322-3328.2005.","journal-title":"J Virol"},{"key":"439_CR10","doi-asserted-by":"publisher","first-page":"1105","DOI":"10.1093\/intimm\/dxp095","volume":"21","author":"S Sakaguchi","year":"2009","unstructured":"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. 10.1093\/intimm\/dxp095.","journal-title":"Int Immunol"},{"key":"439_CR11","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1038\/nri2785","volume":"10","author":"S Sakaguchi","year":"2010","unstructured":"Sakaguchi S, Miyara M, Costantino CM, Hafler DA: FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol. 2010, 10: 490-500. 10.1038\/nri2785.","journal-title":"Nat Rev Immunol"},{"key":"439_CR12","doi-asserted-by":"publisher","first-page":"6545","DOI":"10.4049\/jimmunol.0903879","volume":"184","author":"C Camisaschi","year":"2010","unstructured":"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. 10.4049\/jimmunol.0903879.","journal-title":"J Immunol"},{"key":"439_CR13","doi-asserted-by":"publisher","first-page":"e1002110","DOI":"10.1371\/journal.ppat.1002110","volume":"7","author":"M Nikolova","year":"2011","unstructured":"Nikolova M, Carriere M, Jenabian MA, Limou S, Younas M, Kok A, Hue S, Seddiki N, Hulin A, Delaneau O: CD39\/adenosine pathway is involved in AIDS progression. PLoS Pathog. 2011, 7: e1002110-10.1371\/journal.ppat.1002110.","journal-title":"PLoS Pathog"},{"key":"439_CR14","doi-asserted-by":"publisher","first-page":"5372","DOI":"10.1182\/blood-2010-12-323162","volume":"117","author":"ME Moreno-Fernandez","year":"2011","unstructured":"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. 10.1182\/blood-2010-12-323162.","journal-title":"Blood"},{"key":"439_CR15","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1128\/JVI.01758-10","volume":"85","author":"J Schulze Zur Wiesch","year":"2011","unstructured":"Schulze Zur Wiesch J, Thomssen A, Hartjen P, Toth I, Lehmann C, Meyer-Olson D, Colberg K, Frerk S, Babikir D, Schmiedel S: 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. 10.1128\/JVI.01758-10.","journal-title":"J Virol"},{"key":"439_CR16","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1084\/jem.20062512","volume":"204","author":"S Deaglio","year":"2007","unstructured":"Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M: Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007, 204: 1257-1265. 10.1084\/jem.20062512.","journal-title":"J Exp Med"},{"key":"439_CR17","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1182\/blood-2006-12-064527","volume":"110","author":"G Borsellino","year":"2007","unstructured":"Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Hopner S, Centonze D, Bernardi G, Dell'Acqua ML: Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007, 110: 1225-1232. 10.1182\/blood-2006-12-064527.","journal-title":"Blood"},{"key":"439_CR18","doi-asserted-by":"publisher","first-page":"6348","DOI":"10.1158\/1078-0432.CCR-09-1143","volume":"15","author":"M Mandapathil","year":"2009","unstructured":"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. 10.1158\/1078-0432.CCR-09-1143.","journal-title":"Clin Cancer Res"},{"key":"439_CR19","doi-asserted-by":"publisher","first-page":"7602","DOI":"10.4049\/jimmunol.0901881","volume":"183","author":"JM Fletcher","year":"2009","unstructured":"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. 10.4049\/jimmunol.0901881.","journal-title":"J Immunol"},{"key":"439_CR20","doi-asserted-by":"publisher","first-page":"4708","DOI":"10.4049\/jimmunol.0901036","volume":"184","author":"D Mittag","year":"2010","unstructured":"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. 10.4049\/jimmunol.0901036.","journal-title":"J Immunol"},{"key":"439_CR21","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1055\/s-2005-869527","volume":"31","author":"SC Robson","year":"2005","unstructured":"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. 10.1055\/s-2005-869527.","journal-title":"Semin Thromb Hemost"},{"key":"439_CR22","first-page":"(2):507","volume":"45","author":"AS Lok","year":"2007","unstructured":"Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology. 2007, 45: (2):507-539.","journal-title":"Hepatology"},{"key":"439_CR23","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/0168-8278(91)90084-O","volume":"13","author":"PJ Scheuer","year":"1991","unstructured":"Scheuer PJ: Classification of chronic viral hepatitis: a need for reassessment. J Hepatol. 1991, 13: 372-374. 10.1016\/0168-8278(91)90084-O.","journal-title":"J Hepatol"},{"key":"439_CR24","doi-asserted-by":"publisher","first-page":"5043","DOI":"10.1128\/JVI.01548-07","volume":"82","author":"H Ebinuma","year":"2008","unstructured":"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. 10.1128\/JVI.01548-07.","journal-title":"J Virol"},{"key":"439_CR25","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1007\/s11302-006-9050-y","volume":"3","author":"KM Dwyer","year":"2007","unstructured":"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. 10.1007\/s11302-006-9050-y.","journal-title":"Purinergic Signal"},{"key":"439_CR26","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1002\/eji.200939258","volume":"40","author":"LC Ndhlovu","year":"2010","unstructured":"Ndhlovu LC, Leal FE, Eccles-James IG, Jha AR, Lanteri M, Norris PJ, Barbour JD, Wachter DJ, Andersson J, Tasken K: A novel human CD4+ T-cell inducer subset with potent immunostimulatory properties. Eur J Immunol. 2010, 40: 134-141.","journal-title":"Eur J Immunol"},{"key":"439_CR27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jim.2009.05.004","volume":"346","author":"M Mandapathil","year":"2009","unstructured":"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. 10.1016\/j.jim.2009.05.004.","journal-title":"J Immunol Methods"},{"key":"439_CR28","doi-asserted-by":"publisher","first-page":"2410","DOI":"10.1111\/j.1600-6143.2010.03291.x","volume":"10","author":"KM Dwyer","year":"2010","unstructured":"Dwyer KM, Hanidziar D, Putheti P, Hill PA, Pommey S, McRae JL, Winterhalter A, Doherty G, Deaglio S, Koulmanda M: Expression of CD39 by human peripheral blood CD4+ CD25+ T cells denotes a regulatory memory phenotype. Am J Transplant. 2010, 10: 2410-2420. 10.1111\/j.1600-6143.2010.03291.x.","journal-title":"Am J Transplant"},{"key":"439_CR29","doi-asserted-by":"publisher","first-page":"134","DOI":"10.4049\/jimmunol.0803474","volume":"185","author":"H Moncrieffe","year":"2010","unstructured":"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. 10.4049\/jimmunol.0803474.","journal-title":"J Immunol"},{"key":"439_CR30","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1111\/j.1365-2893.2009.01081.x","volume":"16","author":"N Alatrakchi","year":"2009","unstructured":"Alatrakchi N, Koziel M: Regulatory T cells and viral liver disease. J Viral Hepat. 2009, 16: 223-229. 10.1111\/j.1365-2893.2009.01081.x.","journal-title":"J Viral Hepat"},{"key":"439_CR31","doi-asserted-by":"publisher","first-page":"16788","DOI":"10.1073\/pnas.0902869106","volume":"106","author":"DJ Friedman","year":"2009","unstructured":"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. 10.1073\/pnas.0902869106.","journal-title":"Proc Natl Acad Sci USA"},{"key":"439_CR32","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.it.2008.12.002","volume":"30","author":"MV Sitkovsky","year":"2009","unstructured":"Sitkovsky MV: T regulatory cells: hypoxia-adenosinergic suppression and redirection of the immune response. Trends Immunol. 2009, 30: 102-108. 10.1016\/j.it.2008.12.002.","journal-title":"Trends Immunol"},{"key":"439_CR33","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.it.2007.12.005","volume":"29","author":"MS Bynoe","year":"2008","unstructured":"Bynoe MS, Viret C: Foxp3 + CD4+ T cell-mediated immunosuppression involves extracellular nucleotide catabolism. Trends Immunol. 2008, 29: 99-102. 10.1016\/j.it.2007.12.005.","journal-title":"Trends Immunol"},{"key":"439_CR34","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1084\/jem.191.8.1269","volume":"191","author":"MK Maini","year":"2000","unstructured":"Maini MK, Boni C, Lee CK, Larrubia JR, Reignat S, Ogg GS, King AS, Herberg J, Gilson R, Alisa A: 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. 10.1084\/jem.191.8.1269.","journal-title":"J Exp Med"},{"key":"439_CR35","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1038\/nature07240","volume":"455","author":"K Atarashi","year":"2008","unstructured":"Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K: ATP drives lamina propria T(H)17 cell differentiation. Nature. 2008, 455: 808-812. 10.1038\/nature07240.","journal-title":"Nature"},{"key":"439_CR36","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.trre.2010.01.002","volume":"24","author":"F Salcido-Ochoa","year":"2010","unstructured":"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. 10.1016\/j.trre.2010.01.002.","journal-title":"Transplant Rev (Orlando)"},{"key":"439_CR37","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1016\/j.jhep.2009.12.015","volume":"52","author":"AT Tan","year":"2010","unstructured":"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. 10.1016\/j.jhep.2009.12.015.","journal-title":"J Hepatol"}],"container-title":["BMC Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2172-13-17.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T19:15:26Z","timestamp":1630523726000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcimmunol.biomedcentral.com\/articles\/10.1186\/1471-2172-13-17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,4,11]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2012,12]]}},"alternative-id":["439"],"URL":"https:\/\/doi.org\/10.1186\/1471-2172-13-17","relation":{},"ISSN":["1471-2172"],"issn-type":[{"value":"1471-2172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,4,11]]},"assertion":[{"value":"6 February 2012","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2012","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 April 2012","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"17"}}