{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:10:10Z","timestamp":1764238210465,"version":"3.41.2"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T00:00:00Z","timestamp":1611619200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81460114 81860104"],"award-info":[{"award-number":["81460114 81860104"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012547","name":"Natural Science Foundation of Guangxi Zhuang Autonomous Region","doi-asserted-by":"publisher","award":["0832009"],"award-info":[{"award-number":["0832009"]}],"id":[{"id":"10.13039\/100012547","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p><jats:bold>Objective<\/jats:bold>: This study aimed to investigate the effect of interleukin (IL)-21 and B cell lymphoma protein-6 on germinal center follicular helper T (Tfh) cells and follicular regulatory T (Tfr) cells and its relationship with the clinical features of inflammatory bowel disease (IBD).<\/jats:p><jats:p><jats:bold>Methods<\/jats:bold>: The expression of peripheral blood cytokines IL-21 and Bcl-6 mRNA was detected by reverse transcription\u2013polymerase chain reaction. The distribution characteristics of Tfh and Tfr cells were detected using the triple immunofluorescence staining analysis.<\/jats:p><jats:p><jats:bold>Results<\/jats:bold>: The expression of IL-21 and Bcl-6 mRNA was upregulated in the ulcerative colitis (UC) and Crohn disease (CD) groups compared with that in the control group. Triple immunofluorescence staining showed that the number of Tfh cells in the intestinal germinal center obviously increased in the UC and CD groups compared with that in the control group, whereas the number of Tfr cells reduced.<\/jats:p><jats:p><jats:bold>Conclusion<\/jats:bold>: This study suggested that the Tfr and Tfh cells might be involved in the regulation of IBD. Bcl-6 and IL-21 can regulate the Tfh\/Tfr ratio in the intestinal germinal center, promoting the occurrence and development of IBD.<\/jats:p>","DOI":"10.3389\/fphar.2020.587445","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T08:12:37Z","timestamp":1611648757000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Case Report: IL-21 and Bcl-6 Regulate the Proliferation and Secretion of Tfh and Tfr Cells in the Intestinal Germinal Center of Patients With Inflammatory Bowel Disease"],"prefix":"10.3389","volume":"11","author":[{"given":"Youguang","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodan","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingling","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinping","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingqing","family":"Shi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiyuan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiqiao","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"WeiWei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaojing","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haixing","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Lv","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,26]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10579","DOI":"10.1038\/ncomms10579","article-title":"Follicular regulatory t cells can be specific for the immunizing antigen and derive from naive t cells","volume":"7","author":"Aloulou","year":"2016","journal-title":"Nat. Commun."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.4049\/jimmunol.1300643","article-title":"Notch signaling regulates follicular helper t cell differentiation","volume":"191","author":"Auderset","year":"2013","journal-title":"J. Immunol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1016\/S0140-6736(07)60751-X","article-title":"Inflammatory bowel disease: clinical aspects and established and evolving therapies","volume":"369","author":"Baumgart","year":"2007","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1016\/S0140-6736(12)60026-9","article-title":"Crohn\u2019s disease","volume":"380","author":"Baumgart","year":"2012","journal-title":"Lancet"},{"key":"B5","doi-asserted-by":"publisher","first-page":"1225","DOI":"10.1182\/blood-2006-12-064527","article-title":"Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression","volume":"110","author":"Borsellino","year":"2007","journal-title":"Blood"},{"key":"B6","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.it.2013.01.001","article-title":"T follicular helper cell diversity and plasticity","volume":"34","author":"Cannons","year":"2013","journal-title":"Trends Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1053\/j.gastro.2006.09.053","article-title":"A functional role for interleukin-21 in promoting the synthesis of the t-cell chemoattractant, mip-3\u03b1, by gut epithelial cells","volume":"132","author":"Chelsky","year":"2007","journal-title":"J. Crohns Colitis Suppl."},{"key":"B8","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/j.coi.2013.04.003","article-title":"Dynamic regulation of bcl6 in follicular helper cd4 t (tfh) cells","volume":"25","author":"Choi","year":"2013","journal-title":"Curr. Opin. Immunol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1038\/nm.2426","article-title":"Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions","volume":"17","author":"Chung","year":"2011","journal-title":"Nat. Med."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1084\/jem.20062512","article-title":"Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression","volume":"204","author":"Deaglio","year":"2007","journal-title":"J. Exp. Med."},{"key":"B11","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1111\/j.1365-2567.2011.03487.x","article-title":"The regulation and role of t follicular helper cells in immunity","volume":"134","author":"Deenick","year":"2011","journal-title":"Immunology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"832","DOI":"10.4049\/jimmunol.1500759","article-title":"Circulating follicular regulatory t cells are defective in multiple sclerosis","volume":"195","author":"Dhaeze","year":"2015","journal-title":"J. Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2601","DOI":"10.1002\/art.38735","article-title":"Il-21 promotes germinal center reaction by skewing the tfr\/tfh balance in autoimmune bxd2 mice","volume":"66","author":"Ding","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e17739","DOI":"10.1371\/journal.pone.0017739","article-title":"Il-21 and il-6 are critical for different aspects of b cell immunity and redundantly induce optimal follicular helper cd4 t cell (tfh) differentiation","volume":"6","author":"Eto","year":"2011","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"e0155040","DOI":"10.1371\/journal.pone.0155040","article-title":"Stat3 is important for follicular regulatory t cell differentiation","volume":"11","author":"Hao","year":"2016","journal-title":"PloS One"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1126\/science.1175870","article-title":"Bcl6 and blimp-1 are reciprocal and antagonistic regulators of t follicular helper cell differentiation","volume":"325","author":"Johnston","year":"2009","journal-title":"Science"},{"key":"B17","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1084\/jem.20091738","article-title":"Il-21 acts directly on b cells to regulate bcl-6 expression and germinal center responses","volume":"207","author":"Linterman","year":"2010","journal-title":"J. Exp. Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1111\/j.1600-065X.2012.01121.x","article-title":"T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells","volume":"247","author":"Linterman","year":"2012","journal-title":"Immunol. Rev."},{"key":"B19","doi-asserted-by":"publisher","first-page":"975","DOI":"10.1038\/nm.2425","article-title":"Foxp3+ follicular regulatory t cells control the germinal center response","volume":"17","author":"Linterman","year":"2011","journal-title":"Nat. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1126\/science.1176676","article-title":"Bcl6 mediates the development of t follicular helper cells","volume":"325","author":"Nurieva","year":"2009","journal-title":"Science"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1016\/S0140-6736(12)60150-0","article-title":"Ulcerative colitis","volume":"380","author":"Ord\u00e1s","year":"2012","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1126\/science.1077002","article-title":"A critical role for IL-21 in regulating immunoglobulin production","volume":"298","author":"Ozaki","year":"2002","journal-title":"Science"},{"key":"B23","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/ni.2496","article-title":"The receptor pd-1 controls follicular regulatory t cells in the lymph nodes and blood","volume":"14","author":"Sage","year":"2012","journal-title":"Nat. Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1111\/imr.12411","article-title":"T follicular regulatory cells","volume":"271","author":"Sage","year":"2016","journal-title":"Immunol. Rev."},{"key":"B25","doi-asserted-by":"publisher","first-page":"313","DOI":"10.2174\/187152812800959040","article-title":"Interleukin-21 in immune and allergic diseases","volume":"11","author":"Sarra","year":"2012","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.4049\/jimmunol.1100767","article-title":"Il-21 promotes the pathologic immune response to pneumovirus infection","volume":"188","author":"Spolski","year":"2012","journal-title":"J. Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.4049\/jimmunol.169.5.2461","article-title":"The subpopulation of cd4+cd25+ splenocytes that delays adoptive transfer of diabetes expresses l-selectin and high levels of ccr7","volume":"169","author":"Szanya","year":"2002","journal-title":"J. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"9355","DOI":"10.1007\/s13277-014-2208-2","article-title":"Circulating follicular helper t cells in crohn\u2019s disease (cd) and cd-associated colorectal cancer","volume":"35","author":"Wang","year":"2014","journal-title":"Tumour Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"4553","DOI":"10.4049\/jimmunol.1101328","article-title":"Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells","volume":"187","author":"Wollenberg","year":"2011","journal-title":"J. Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.3892\/mmr.2014.2824","article-title":"Interleukin\u201121 promotes the development of ulcerative colitis and regulates the proliferation and secretion of follicular T helper cells in the colitides microenvironment","volume":"11","author":"Yu","year":"2015","journal-title":"Mol. Med. Rep."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.587445\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T08:12:41Z","timestamp":1611648761000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2020.587445\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,26]]},"references-count":30,"alternative-id":["10.3389\/fphar.2020.587445"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2020.587445","relation":{},"ISSN":["1663-9812"],"issn-type":[{"type":"electronic","value":"1663-9812"}],"subject":[],"published":{"date-parts":[[2021,1,26]]},"article-number":"587445"}}