{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T00:28:04Z","timestamp":1773275284246,"version":"3.50.1"},"reference-count":48,"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":[[2009,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>CD45RO<jats:sup>+<\/jats:sup>T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161,<jats:italic>P<\/jats:italic>&lt; 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121,<jats:italic>P<\/jats:italic>&lt; 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction of<jats:italic>bona fide<\/jats:italic>FOXP3<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants of<jats:italic>CTLA4<\/jats:italic>and<jats:italic>TGF\u03b2<\/jats:italic>were associated with the decreased frequency of Treg in PBMC, while<jats:italic>FOXP3<\/jats:italic>gene variants were associated with affection status, but not with Treg frequency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3<jats:sup>+<\/jats:sup>CD25<jats:sup>-<\/jats:sup>into FOXP3<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>T cells. Treg frequency is highly heritable within SLE families, with specific variants of the<jats:italic>CTLA4<\/jats:italic>and<jats:italic>TGF\u03b2<\/jats:italic>genes contributing to this trait, while<jats:italic>FOXP3<\/jats:italic>contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1471-2172-10-5","type":"journal-article","created":{"date-parts":[[2009,1,27]],"date-time":"2009-01-27T19:13:50Z","timestamp":1233083630000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGF\u03b2 gene variants"],"prefix":"10.1186","volume":"10","author":[{"given":"Marta","family":"Barreto","sequence":"first","affiliation":[]},{"given":"Ricardo C","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Lara","family":"Louren\u00e7o","sequence":"additional","affiliation":[]},{"given":"Maria F","family":"Moraes-Fontes","sequence":"additional","affiliation":[]},{"given":"Eug\u00e9nia","family":"Santos","sequence":"additional","affiliation":[]},{"given":"Miguel","family":"Alves","sequence":"additional","affiliation":[]},{"given":"Cl\u00e1udia","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Berta","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Rita","family":"Andreia","sequence":"additional","affiliation":[]},{"given":"Jo\u00e3o F","family":"Viana","sequence":"additional","affiliation":[]},{"given":"Carlos","family":"Vasconcelos","sequence":"additional","affiliation":[]},{"given":"Lu\u00edsa","family":"Mota-Vieira","sequence":"additional","affiliation":[]},{"given":"Carlos","family":"Ferreira","sequence":"additional","affiliation":[]},{"given":"Jocelyne","family":"Demengeot","sequence":"additional","affiliation":[]},{"given":"Astrid M","family":"Vicente","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2009,1,27]]},"reference":[{"key":"225_CR1","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1126\/science.1900951","volume":"251","author":"B Rocha","year":"1991","unstructured":"Rocha B, von Boehmer H: Peripheral selection of the T cell repertoire. Science. 1991, 251: 1225-8.","journal-title":"Science"},{"key":"225_CR2","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1126\/science.280.5361.243","volume":"280","author":"L Van Parijs","year":"1998","unstructured":"Van Parijs L, Abbas AK: Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science. 1998, 280: 243-8.","journal-title":"Science"},{"key":"225_CR3","doi-asserted-by":"crossref","first-page":"5317","DOI":"10.4049\/jimmunol.162.9.5317","volume":"162","author":"M Itoh","year":"1999","unstructured":"Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S: Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 1999, 162: 5317-26.","journal-title":"J Immunol"},{"key":"225_CR4","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1146\/annurev.immunol.21.120601.141122","volume":"22","author":"S Sakaguchi","year":"2004","unstructured":"Sakaguchi S: Naturally Arising CD4+ Regulatory T Cells for Immunologic Self-Tolerance and Negative Control of Immune Responses. Annu Rev Immunol. 2004, 22: 531-562.","journal-title":"Annu Rev Immunol"},{"key":"225_CR5","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1111\/j.1365-2249.2006.03173.x","volume":"145","author":"WT Hsu","year":"2006","unstructured":"Hsu WT, Suen JL, Chiang BL: The role of CD4CD25 T cells in autoantibody production in murine lupus. Clin Exp Immunol. 2006, 145: 513-9.","journal-title":"Clin Exp Immunol"},{"key":"225_CR6","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1084\/jem.194.4.427","volume":"194","author":"SJ Bensinger","year":"2001","unstructured":"Bensinger SJ, Bandeira A, Jordan MS, Caton AJ, Laufer TM: Major histocompatibility complex class II-positive cortical epithelium mediates the selection of CD4(+)25(+) immunoregulatory T cells. J Exp Med. 2001, 194: 427-38.","journal-title":"J Exp Med"},{"key":"225_CR7","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1126\/science.270.5238.985","volume":"270","author":"P Waterhouse","year":"1995","unstructured":"Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW: Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995, 270: 985-8.","journal-title":"Science"},{"key":"225_CR8","doi-asserted-by":"publisher","first-page":"6645","DOI":"10.4049\/jimmunol.173.11.6645","volume":"173","author":"H Kwon","year":"2004","unstructured":"Kwon H, Jun HS, Khil LY, Yoon JW: Role of ctla-4 in the activation of single- and double-positive thymocytes. J Immunol. 2004, 173: 6645-53.","journal-title":"J Immunol"},{"key":"225_CR9","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/0470871628.ch5","volume":"252","author":"E Boden","year":"2003","unstructured":"Boden E, Tang Q, Bour-Jordan H, Bluestone JA: The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells. Novartis Found Symp. 2003, 252: 55-63.","journal-title":"Novartis Found Symp"},{"key":"225_CR10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/359693a0","volume":"359","author":"MM Shull","year":"1992","unstructured":"Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D, et al.: Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992, 359: 693-9.","journal-title":"Nature"},{"key":"225_CR11","doi-asserted-by":"publisher","first-page":"4572","DOI":"10.1073\/pnas.0400810101","volume":"101","author":"Y Peng","year":"2004","unstructured":"Peng Y, Laouar Y, Li MO, Green EA, Flavell RA: TGF-beta regulates in vivo expansion of Foxp3-expressing CD4+CD25+ regulatory T cells responsible for protection against diabetes. Proc Natl Acad Sci USA. 2004, 101: 4572-7.","journal-title":"Proc Natl Acad Sci USA"},{"key":"225_CR12","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1084\/jem.193.11.1303","volume":"193","author":"D Dieckmann","year":"2001","unstructured":"Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G: Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001, 193: 1303-10.","journal-title":"J Exp Med"},{"key":"225_CR13","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/S0896-8411(03)00121-5","volume":"21","author":"JC Crispin","year":"2003","unstructured":"Crispin JC, Martinez A, Alcocer-Varela J: Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun. 2003, 21: 273-6.","journal-title":"J Autoimmun"},{"key":"225_CR14","doi-asserted-by":"publisher","first-page":"2579","DOI":"10.4049\/jimmunol.178.4.2579","volume":"178","author":"X Valencia","year":"2007","unstructured":"Valencia X, Yarboro C, Illei G, Lipsky PE: Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol. 2007, 178: 2579-88.","journal-title":"J Immunol"},{"key":"225_CR15","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1172\/JCI0213605","volume":"109","author":"A Kukreja","year":"2002","unstructured":"Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B, et al.: Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002, 109: 131-40.","journal-title":"J Clin Invest"},{"key":"225_CR16","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1084\/jem.20031579","volume":"199","author":"V Viglietta","year":"2004","unstructured":"Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA: Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med. 2004, 199: 971-9.","journal-title":"J Exp Med"},{"key":"225_CR17","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1126\/science.1079490","volume":"299","author":"S Hori","year":"2003","unstructured":"Hori S, Nomura T, Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003, 299: 1057-61.","journal-title":"Science"},{"key":"225_CR18","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1136\/jmg.39.8.537","volume":"39","author":"RS Wildin","year":"2002","unstructured":"Wildin RS, Smyk-Pearson S, Filipovich AH: Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002, 39: 537-45.","journal-title":"J Med Genet"},{"key":"225_CR19","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1016\/j.coi.2003.09.011","volume":"15","author":"M Gavin","year":"2003","unstructured":"Gavin M, Rudensky A: Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr Opin Immunol. 2003, 15: 690-6.","journal-title":"Curr Opin Immunol"},{"key":"225_CR20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/S0092-8674(00)81108-3","volume":"85","author":"BL Kotzin","year":"1996","unstructured":"Kotzin BL: Systemic lupus erythematosus. Cell. 1996, 85: 303-6.","journal-title":"Cell"},{"key":"225_CR21","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1097\/00002281-199305050-00004","volume":"5","author":"CS Via","year":"1993","unstructured":"Via CS, Handwerger BS: B-cell and T-cell function in systemic lupus erythematosus. Curr Opin Rheumatol. 1993, 5: 570-4.","journal-title":"Curr Opin Rheumatol"},{"key":"225_CR22","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1136\/ard.59.4.243","volume":"59","author":"GS Dean","year":"2000","unstructured":"Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA: Cytokines and systemic lupus erythematosus. Ann Rheum Dis. 2000, 59: 243-51.","journal-title":"Ann Rheum Dis"},{"key":"225_CR23","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1002\/art.1780400928","volume":"40","author":"MC Hochberg","year":"1997","unstructured":"Hochberg MC: Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997, 40: 1725-","journal-title":"Arthritis Rheum"},{"key":"225_CR24","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1002\/art.1780350606","volume":"35","author":"C Bombardier","year":"1992","unstructured":"Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH: Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992, 35: 630-40.","journal-title":"Arthritis Rheum"},{"key":"225_CR25","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/S0140-6736(96)90539-5","volume":"347","author":"AE Johnson","year":"1996","unstructured":"Johnson AE, Gordon C, Hobbs FD, Bacon PA: Undiagnosed systemic lupus erythematosus in the community. Lancet. 1996, 347: 367-9.","journal-title":"Lancet"},{"key":"225_CR26","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jaut.2005.05.004","volume":"25","author":"R Ferreira","year":"2005","unstructured":"Ferreira R, Barreto M, Santos E, Pereira C, Martins B, Andreia R, Crespo F, Viana JF, Vasconcelos C, Ferreira C, et al.: Heritable factors shape natural human IgM reactivity to Ro60\/SS-A and may predispose for SLE-asssociated IgG anti-Ro and anti-La autoantibody production. J Autoimmun. 2005, 25: 155-163.","journal-title":"J Autoimmun"},{"key":"225_CR27","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1038\/sj.ejhg.5201214","volume":"12","author":"M Barreto","year":"2004","unstructured":"Barreto M, Santos E, Ferreira R, Fesel C, Fontes MF, Pereira C, Martins B, Andreia R, Viana JF, Crespo F, et al.: Evidence for CTLA4 as a susceptibility gene for systemic lupus erythematosus. Eur J Hum Genet. 2004, 12: 620-6.","journal-title":"Eur J Hum Genet"},{"key":"225_CR28","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1093\/hmg\/8.1.93","volume":"8","author":"DJ Grainger","year":"1999","unstructured":"Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD: Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet. 1999, 8: 93-7.","journal-title":"Hum Mol Genet"},{"key":"225_CR29","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.cyto.2003.08.007","volume":"24","author":"CG Tag","year":"2003","unstructured":"Tag CG, Mengsteab S, Hellerbrand C, Lammert F, Gressner AM, Weiskirchen R: Analysis of the transforming growth factor-beta1 (TGF-beta1) codon 25 gene polymorphism by LightCycler-analysis in patients with chronic hepatitis C infection. Cytokine. 2003, 24: 173-81.","journal-title":"Cytokine"},{"key":"225_CR30","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s00251-003-0559-8","volume":"55","author":"WM Bassuny","year":"2003","unstructured":"Bassuny WM, Ihara K, Sasaki Y, Kuromaru R, Kohno H, Matsuura N, Hara T: A functional polymorphism in the promoter\/enhancer region of the FOXP3\/Scurfin gene associated with type 1 diabetes. Immunogenetics. 2003, 55: 149-56.","journal-title":"Immunogenetics"},{"key":"225_CR31","first-page":"435","volume":"30","author":"M Fedetz","year":"2003","unstructured":"Fedetz M, Matesanz F, Caliz R, Ferrer MA, Collado MD, Alcina A, Martin J: Lack of association between -384 and 114 IL-2 gene polymorphisms and rheumatoid arthritis. J Rheumatol. 2003, 30: 435-7.","journal-title":"J Rheumatol"},{"key":"225_CR32","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1007\/s00415-006-0416-4","volume":"254","author":"F Matesanz","year":"2007","unstructured":"Matesanz F, Caro-Maldonado A, Fedetz M, Fernandez O, Milne RL, Guerrero M, Delgado C, Alcina A: IL2RA\/CD25 polymorphisms contribute to multiple sclerosis susceptibility. J Neurol. 2007, 254: 682-4.","journal-title":"J Neurol"},{"key":"225_CR33","doi-asserted-by":"publisher","first-page":"1198","DOI":"10.1086\/301844","volume":"62","author":"L Almasy","year":"1998","unstructured":"Almasy L, Blangero J: Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet. 1998, 62: 1198-211.","journal-title":"Am J Hum Genet"},{"key":"225_CR34","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1093\/bioinformatics\/16.2.182","volume":"16","author":"GR Abecasis","year":"2000","unstructured":"Abecasis GR, Cookson WO: GOLD \u2013 graphical overview of linkage disequilibrium. Bioinformatics. 2000, 16: 182-3.","journal-title":"Bioinformatics"},{"key":"225_CR35","doi-asserted-by":"publisher","first-page":"1285","DOI":"10.1084\/jem.193.11.1285","volume":"193","author":"H Jonuleit","year":"2001","unstructured":"Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH: Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med. 2001, 193: 1285-94.","journal-title":"J Exp Med"},{"key":"225_CR36","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1084\/jem.20011756","volume":"195","author":"S Kimmig","year":"2002","unstructured":"Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Mowes B, Radbruch A, Thiel A: Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med. 2002, 195: 789-94.","journal-title":"J Exp Med"},{"key":"225_CR37","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1093\/rheumatology\/kem154","volume":"46","author":"K Tenbrock","year":"2007","unstructured":"Tenbrock K, Juang YT, Kyttaris VC, Tsokos GC: Altered signal transduction in SLE T cells. Rheumatology (Oxford). 2007, 46: 1525-30.","journal-title":"Rheumatology (Oxford)"},{"key":"225_CR38","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/ni1263","volume":"6","author":"JD Fontenot","year":"2005","unstructured":"Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY: A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005, 6: 1142-51.","journal-title":"Nat Immunol"},{"key":"225_CR39","doi-asserted-by":"publisher","first-page":"R335","DOI":"10.1186\/ar1192","volume":"6","author":"D Cao","year":"2004","unstructured":"Cao D, Vollenhoven Rv R, Klareskog L, Trollmo C, Malmstrom V: CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther. 2004, 6: R335-46.","journal-title":"Arthritis Res Ther"},{"key":"225_CR40","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1182\/blood-2007-03-079947","volume":"111","author":"A Ephrem","year":"2008","unstructured":"Ephrem A, Chamat S, Miquel C, Fisson S, Mouthon L, Caligiuri G, Delignat S, Elluru S, Bayry J, Lacroix-Desmazes S, et al.: Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis. Blood. 2008, 111: 715-22.","journal-title":"Blood"},{"key":"225_CR41","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1084\/jem.192.2.295","volume":"192","author":"S Read","year":"2000","unstructured":"Read S, Malmstrom V, Powrie F: Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000, 192: 295-302.","journal-title":"J Exp Med"},{"key":"225_CR42","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1084\/jem.192.2.303","volume":"192","author":"T Takahashi","year":"2000","unstructured":"Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000, 192: 303-10.","journal-title":"J Exp Med"},{"key":"225_CR43","doi-asserted-by":"publisher","first-page":"2888","DOI":"10.1002\/1521-4141(2002010)32:10<2888::AID-IMMU2888>3.0.CO;2-F","volume":"32","author":"CN Manzotti","year":"2002","unstructured":"Manzotti CN, Tipping H, Perry LC, Mead KI, Blair PJ, Zheng Y, Sansom DM: Inhibition of human T cell proliferation by CTLA-4 utilizes CD80 and requires CD25+ regulatory T cells. Eur J Immunol. 2002, 32: 2888-96.","journal-title":"Eur J Immunol"},{"key":"225_CR44","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1084\/jem.20020110","volume":"196","author":"F Annunziato","year":"2002","unstructured":"Annunziato F, Cosmi L, Liotta F, Lazzeri E, Manetti R, Vanini V, Romagnani P, Maggi E, Romagnani S: Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med. 2002, 196: 379-87.","journal-title":"J Exp Med"},{"key":"225_CR45","volume-title":"Eur J Immunol","author":"Q Tang","year":"2004","unstructured":"Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA: Distinct roles of CTLA-4 and TGF-beta in CD4(+)CD25(+) regulatory T cell function. Eur J Immunol. 2004"},{"key":"225_CR46","doi-asserted-by":"publisher","first-page":"6526","DOI":"10.4049\/jimmunol.173.11.6526","volume":"173","author":"S Huber","year":"2004","unstructured":"Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M: Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol. 2004, 173: 6526-31.","journal-title":"J Immunol"},{"key":"225_CR47","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.1111\/j.1365-2133.2008.08555.x","volume":"158","author":"H Su","year":"2008","unstructured":"Su H, Ye DQ, Wang BL, Fang XH, Chen J, Wang Q, Li WX, Zhang N: Transforming growth factor-beta1-induced CD4+CD25+ regulatory T cells in vitro reverse and prevent a murine lupus-like syndrome of chronic graft-versus-host disease. Br J Dermatol. 2008, 158: 1197-209.","journal-title":"Br J Dermatol"},{"key":"225_CR48","first-page":"165","volume":"41","author":"LY Lu","year":"2008","unstructured":"Lu LY, Chu JJ, Lu PJ, Sung PK, Hsu CM, Tseng JC: Expression of intracellular transforming growth factor-beta1 in CD4(+)CD25(+) cells in patients with systemic lupus erythematosus. J Microbiol Immunol Infect. 2008, 41: 165-73.","journal-title":"J Microbiol Immunol Infect"}],"container-title":["BMC Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/1471-2172-10-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T19:43:37Z","timestamp":1684871017000},"score":1,"resource":{"primary":{"URL":"https:\/\/bmcimmunol.biomedcentral.com\/articles\/10.1186\/1471-2172-10-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,1,27]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2009,12]]}},"alternative-id":["225"],"URL":"https:\/\/doi.org\/10.1186\/1471-2172-10-5","relation":{},"ISSN":["1471-2172"],"issn-type":[{"value":"1471-2172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,1,27]]},"assertion":[{"value":"4 September 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"5"}}