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The benefit of such non\u2010inflammatory B\u2010cell responses is apparent in the hyporesponsive state of patients with helminth infections such as Onchocerciasis. Here, we investigated the mechanisms involved to induce IgG4, within B:Tr\u2010cell co\u2010cultures, using IL\u201010\u2010producing tetanus\u2010toxoid\u2010specific regulatory T cell lines and clones (Tr\u2010TCC) from human PBMC. During the generation process, we found that increasing Foxp3 levels in regulatory T cell lines correlated with their ability to induce IgG4 in B cells. Using Tr\u2010TCC, we found that blocking glucocorticoid\u2010induced tumour necrosis factor receptor\u2010related protein (GITR) molecules selectively prevented IgG4 production as did neutralizing Ab to glucocorticoid\u2010induced tumour necrosis factor receptor\u2010related protein ligand (GITR\u2010L), IL\u201010 and TGF\u2010\u03b2. Furthermore, the prevention of IgG4 induction by anti\u2010GITR Ab was reversed by excess rIL\u201010 but not rTGF\u2010\u03b2. In contrast, anti\u2010ICOS and anti\u2010CTLA\u20104 Abs had no effect. When compared with Tr\u2010TCC, freshly isolated CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup> T cells, but not effector T cell populations, induced low levels of IgG4, which were also blocked by anti\u2010GITR and anti\u2010GITR\u2010L Ab. Thus, the mechanism of IgG4 induction by regulatory cells involves GITR\u2013GITR\u2010L interactions, IL\u201010 and TGF\u2010\u03b2.<\/jats:p>","DOI":"10.1002\/eji.200838193","type":"journal-article","created":{"date-parts":[[2008,10,16]],"date-time":"2008-10-16T11:14:24Z","timestamp":1224155664000},"page":"3101-3113","source":"Crossref","is-referenced-by-count":103,"title":["Tr1 and naturally occurring regulatory T cells induce IgG4 in B cells through GITR\/GITR\u2010L interaction, IL\u201010 and TGF\u2010\u03b2"],"prefix":"10.1002","volume":"38","author":[{"given":"Judith S.","family":"Satoguina","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomabu","family":"Adjobimey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Arndts","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jochen","family":"Hoch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Oldenburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Layland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Achim","family":"Hoerauf","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2008,11,7]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/39614"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/12.5.623"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20020394"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.9.1213"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2006.00420.x"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021139"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.2741\/2840"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni904"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425818"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1867"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.12.6216"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2334901100"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gene.6364026"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.18.11935-11942.2005"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/378620a0"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni846"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1457"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1563"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI31911"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.8.5008"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni759"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.8.4686"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050940"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.8.4718"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(02)00014-X"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2005.03.036"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1998.00732.x"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.09.004"},{"key":"e_1_2_6_30_2","first-page":"415","article-title":"Inhibition of complement activation by IgG4 antibodies","volume":"64","author":"van der Zee J. 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