{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T19:17:04Z","timestamp":1790363824475,"version":"4.1.0"},"reference-count":107,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T00:00:00Z","timestamp":1631491200000},"content-version":"vor","delay-in-days":255,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007322","name":"Binzhou Medical University","doi-asserted-by":"publisher","award":["BY2016KYQD21"],"award-info":[{"award-number":["BY2016KYQD21"]}],"id":[{"id":"10.13039\/501100007322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007322","name":"Binzhou Medical University","doi-asserted-by":"publisher","award":["BY2017KYQD15"],"award-info":[{"award-number":["BY2017KYQD15"]}],"id":[{"id":"10.13039\/501100007322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2017BC047"],"award-info":[{"award-number":["ZR2017BC047"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2017BH078"],"award-info":[{"award-number":["ZR2017BH078"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81901380"],"award-info":[{"award-number":["81901380"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81701192"],"award-info":[{"award-number":["81701192"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2021,1]]},"abstract":"<jats:p>Follicular helper CD4<jats:sup>+<\/jats:sup> T (TFH) cells are a specialized subset of effector T cells that play a central role in orchestrating adaptive immunity. TFH cells mainly promote germinal center (GC) formation, provide help to B cells for immunoglobulin affinity maturation and class\u2010switch recombination of B cells, and facilitate production of long\u2010lived plasma cells and memory B cells. TFH cells express the nuclear transcriptional repressor B cell lymphoma 6 (Bcl\u20106), the chemokine (C\u2010X\u2010C motif) receptor 5 (CXCR5), the CD28 family members programmed cell death protein\u20101 (PD\u20101) and inducible costimulator (ICOS) and are also responsible for the secretion of interleukin\u201021 (IL\u201021) and IL\u20104. Follicular regulatory CD4+ T (TFR) cells, as a regulatory counterpart of TFH cells, participate in the regulation of GC reactions. TFR cells not only express markers of TFH cells but also express markers of regulatory T (Treg) cells containing FOXP3, glucocorticoid\u2010induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte antigen 4 (CTLA\u20104), and IL\u201010, hence owing to the dual characteristic of TFH cells and Treg cells. ICOS, expressed on activated CD4<jats:sup>+<\/jats:sup> effector T cells, participates in T cell activation, differentiation, and effector process. The expression of ICOS is highest on TFH and TFR cells, indicating it as a key regulator of humoral immunity. Multiple sclerosis (MS) is a severe autoimmune disease that affects the central nervous system and results in disability, mediated by autoreactive T cells with evolving evidence of a remarkable contribution from humoral responses. This review summarizes recent advances regarding TFH cells, TFR cells, and ICOS, as well as their functional characteristics in relation to MS.<\/jats:p>","DOI":"10.1155\/2021\/2058964","type":"journal-article","created":{"date-parts":[[2021,9,13]],"date-time":"2021-09-13T15:25:09Z","timestamp":1631546709000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Follicular Helper CD4<sup>+<\/sup> T Cells, Follicular Regulatory CD4<sup>+<\/sup> T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis"],"prefix":"10.1155","volume":"2021","author":[{"given":"Xue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruli","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongliang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxwell","family":"Ahiafor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-0922","authenticated-orcid":false,"given":"Jinbo","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7787-3702","authenticated-orcid":false,"given":"Xueli","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,9,13]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12740"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101400"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.04.011"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01637"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11892-016-0770-2"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2013.55"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.10.004"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.91487"},{"key":"e_1_2_9_9_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00520"},{"key":"e_1_2_9_10_2","article-title":"The many faces of CD4(+) T cells: immunological and structural characteristics","volume":"22","author":"Chatzileontiadou D. S. M.","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2013.01.001"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00480"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/638968"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1111\/all.12878"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01793"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07345"},{"key":"e_1_2_9_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.01.010"},{"key":"e_1_2_9_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1175870"},{"key":"e_1_2_9_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120994"},{"key":"e_1_2_9_20_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103246"},{"key":"e_1_2_9_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.94"},{"key":"e_1_2_9_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3447"},{"key":"e_1_2_9_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.09.007"},{"key":"e_1_2_9_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-019-0254-2"},{"key":"e_1_2_9_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13282"},{"key":"e_1_2_9_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002828"},{"key":"e_1_2_9_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.02.020"},{"key":"e_1_2_9_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.12.012"},{"key":"e_1_2_9_29_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201507-1499OC"},{"key":"e_1_2_9_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxv007"},{"key":"e_1_2_9_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00305"},{"key":"e_1_2_9_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3384"},{"key":"e_1_2_9_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2496"},{"key":"e_1_2_9_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.06.015"},{"key":"e_1_2_9_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13075-014-0471-7"},{"key":"e_1_2_9_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxv079"},{"key":"e_1_2_9_37_2","doi-asserted-by":"publisher","DOI":"10.1002\/cti2.1106"},{"key":"e_1_2_9_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2426"},{"key":"e_1_2_9_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2015.05.005"},{"key":"e_1_2_9_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/icb.2013.69"},{"key":"e_1_2_9_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12411"},{"key":"e_1_2_9_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.12.005"},{"key":"e_1_2_9_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aan1487"},{"key":"e_1_2_9_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10579"},{"key":"e_1_2_9_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12739"},{"key":"e_1_2_9_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14647"},{"key":"e_1_2_9_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.40424"},{"key":"e_1_2_9_48_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.12774"},{"key":"e_1_2_9_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2017.07.004"},{"key":"e_1_2_9_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2020.06.003"},{"key":"e_1_2_9_51_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(200004)30:4<1040::AID-IMMU1040>3.0.CO;2-6"},{"key":"e_1_2_9_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/35051107"},{"key":"e_1_2_9_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2010.01.001"},{"key":"e_1_2_9_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri727"},{"key":"e_1_2_9_55_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24203"},{"key":"e_1_2_9_56_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00304"},{"key":"e_1_2_9_57_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-0662"},{"key":"e_1_2_9_58_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2015.05.014"},{"key":"e_1_2_9_59_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M707693200"},{"key":"e_1_2_9_60_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.02104"},{"key":"e_1_2_9_61_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3000448"},{"key":"e_1_2_9_62_2","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-021-00164-9"},{"key":"e_1_2_9_63_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02470"},{"key":"e_1_2_9_64_2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12771"},{"key":"e_1_2_9_65_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.4798"},{"key":"e_1_2_9_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.01.017"},{"key":"e_1_2_9_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3050"},{"key":"e_1_2_9_68_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12058"},{"key":"e_1_2_9_69_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2014.01.008"},{"key":"e_1_2_9_70_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature13803"},{"key":"e_1_2_9_71_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1100898108"},{"key":"e_1_2_9_72_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/827480"},{"key":"e_1_2_9_73_2","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217646"},{"key":"e_1_2_9_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2012.12.001"},{"key":"e_1_2_9_75_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.25032"},{"key":"e_1_2_9_76_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2003"},{"key":"e_1_2_9_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri1714"},{"key":"e_1_2_9_78_2","doi-asserted-by":"publisher","DOI":"10.1111\/all.13602"},{"key":"e_1_2_9_79_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2020.03.036"},{"key":"e_1_2_9_80_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2017.11.008"},{"key":"e_1_2_9_81_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130604"},{"key":"e_1_2_9_82_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.013"},{"key":"e_1_2_9_83_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1401483"},{"key":"e_1_2_9_84_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19103233"},{"key":"e_1_2_9_85_2","doi-asserted-by":"publisher","DOI":"10.1111\/joim.13215"},{"key":"e_1_2_9_86_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30481-1"},{"key":"e_1_2_9_87_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-020-10275-x"},{"key":"e_1_2_9_88_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25927"},{"key":"e_1_2_9_89_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0135-x"},{"key":"e_1_2_9_90_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00944"},{"key":"e_1_2_9_91_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134523"},{"key":"e_1_2_9_92_2","doi-asserted-by":"publisher","DOI":"10.1371\/annotation\/b4e623eb-4950-48d9-8d85-8d70426d95a3"},{"key":"e_1_2_9_93_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01097"},{"key":"e_1_2_9_94_2","doi-asserted-by":"publisher","DOI":"10.3109\/1547691X.2015.1089343"},{"key":"e_1_2_9_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2019.09.003"},{"key":"e_1_2_9_96_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1500759"},{"key":"e_1_2_9_97_2","doi-asserted-by":"publisher","DOI":"10.1177\/1352458518779951"},{"key":"e_1_2_9_98_2","doi-asserted-by":"publisher","DOI":"10.1080\/08916934.2017.1284821"},{"key":"e_1_2_9_99_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-14118-w"},{"key":"e_1_2_9_100_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007042"},{"key":"e_1_2_9_101_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801425"},{"key":"e_1_2_9_102_2","doi-asserted-by":"publisher","DOI":"10.1177\/1352458518790417"},{"key":"e_1_2_9_103_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00382"},{"key":"e_1_2_9_104_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-021-02076-4"},{"key":"e_1_2_9_105_2","doi-asserted-by":"publisher","DOI":"10.1038\/89750"},{"key":"e_1_2_9_106_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-015-0068-1"},{"key":"e_1_2_9_107_2","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000272"}],"container-title":["Mediators of Inflammation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/mi\/2021\/2058964.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/mi\/2021\/2058964.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/2021\/2058964","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T09:14:41Z","timestamp":1756372481000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/2021\/2058964"}},"subtitle":[],"editor":[{"given":"Joilson O.","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,1]]},"references-count":107,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1]]}},"alternative-id":["10.1155\/2021\/2058964"],"URL":"https:\/\/doi.org\/10.1155\/2021\/2058964","archive":["Portico"],"relation":{},"ISSN":["0962-9351","1466-1861"],"issn-type":[{"value":"0962-9351","type":"print"},{"value":"1466-1861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1]]},"assertion":[{"value":"2021-04-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-08-26","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2058964"}}