{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T03:30:08Z","timestamp":1782185408067,"version":"3.54.5"},"reference-count":96,"publisher":"The Royal Society","issue":"10","license":[{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:00:00Z","timestamp":1727740800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["Open Biol."],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:p>\n                    Immunologic self-tolerance involves signals from co-inhibitory receptors. Several T cell co-inhibitors, including PD-1, are expressed upon activation, whereas CD5 and BTLA are expressed constitutively. The relationship between constitutively expressed co-inhibitors and when they are needed is unknown. Deletion of\n                    <jats:italic>Btla<\/jats:italic>\n                    demonstrated BTLA regulates CD5 expression. Loss of BTLA signals, but not signalling by its ligand, HVEM, leads to increased CD5 expression. Higher CD5 expression set during thymic selection is associated with increased self-recognition, suggesting that BTLA might be needed early to establish self-tolerance. We found that BTLA and PD-1 were needed post-thymic selection in recent thymic emigrants (RTE). RTE lacking BTLA caused a CD4 T cell and MHC class II dependent multi-organ autoimmune disease. Together, our findings identify a negative regulatory pathway between two constitutively expressed co-inhibitors, calibrating their expression. Expression of constitutive and induced co-inhibitory receptors is needed early to establish tolerance in the periphery for RTE.\n                  <\/jats:p>","DOI":"10.1098\/rsob.240178","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T20:05:11Z","timestamp":1730232311000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Internal regulation between constitutively expressed T cell co-inhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants"],"prefix":"10.1098","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0886-9678","authenticated-orcid":true,"given":"Adeolu O.","family":"Adegoke","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Govindarajan","family":"Thangavelu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta, Edmonton, AB, Canada"},{"name":"Alberta Diabetes and Transplant Institutes, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Fang","family":"Chou","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos I.","family":"Petersen","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta, Edmonton, AB, Canada"},{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyokazu","family":"Kakugawa","sequence":"additional","affiliation":[{"name":"Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia F.","family":"May","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Joannou","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingyang","family":"Wang","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristofor K.","family":"Ellestad","sequence":"additional","affiliation":[{"name":"Alberta Diabetes and Transplant Institutes, University of Alberta, Edmonton, AB, Canada"},{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[{"name":"JJP Biologics, Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Bretscher","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Cheroutre","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"},{"name":"Laboratory for Immune Crosstalk, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6318-6445","authenticated-orcid":true,"given":"Mitchell","family":"Kronenberg","sequence":"additional","affiliation":[{"name":"La Jolla Institute for Immunology, La Jolla, CA 92037, USA"},{"name":"Department of Molecular Biology, University of California San Diego, La Jolla, CA 92093, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-3746","authenticated-orcid":true,"given":"Troy A.","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1733-4237","authenticated-orcid":true,"given":"Colin C.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alberta, Edmonton, AB, Canada"},{"name":"Alberta Diabetes and Transplant Institutes, University of Alberta, Edmonton, AB, Canada"},{"name":"Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"e_1_3_8_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/309322a0"},{"key":"e_1_3_8_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/sji.13144"},{"key":"e_1_3_8_4_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-3083.1996.d01-267.x"},{"key":"e_1_3_8_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01289"},{"key":"e_1_3_8_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1992.tb05481.x"},{"key":"e_1_3_8_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(94)90071-X"},{"key":"e_1_3_8_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.152.2.280"},{"key":"e_1_3_8_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni944"},{"key":"e_1_3_8_10_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100619"},{"key":"e_1_3_8_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.19.4.2903"},{"key":"e_1_3_8_12_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.157.1.202"},{"key":"e_1_3_8_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.3.802"},{"key":"e_1_3_8_14_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.84.1.204"},{"key":"e_1_3_8_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/0968-0004(94)90165-1"},{"key":"e_1_3_8_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/351662a0"},{"key":"e_1_3_8_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.03.011"},{"key":"e_1_3_8_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.003"},{"key":"e_1_3_8_19_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.3.811"},{"key":"e_1_3_8_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/10.8.1185"},{"key":"e_1_3_8_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5294.1906"},{"key":"e_1_3_8_22_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199907)29:07<2119::AID-IMMU2119>3.0.CO;2-F"},{"key":"e_1_3_8_23_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.5.3158"},{"key":"e_1_3_8_24_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.4.1279"},{"key":"e_1_3_8_25_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903823"},{"key":"e_1_3_8_26_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.170.9.4623"},{"key":"e_1_3_8_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19051295"},{"key":"e_1_3_8_28_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.6.3377"},{"key":"e_1_3_8_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.11.070"},{"key":"e_1_3_8_30_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.10.6420"},{"key":"e_1_3_8_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1144"},{"key":"e_1_3_8_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.956694"},{"key":"e_1_3_8_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.23674"},{"key":"e_1_3_8_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110553"},{"key":"e_1_3_8_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830240733"},{"key":"e_1_3_8_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1922525117"},{"key":"e_1_3_8_37_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2301"},{"key":"e_1_3_8_38_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.166.9.5464"},{"key":"e_1_3_8_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2012.09.011"},{"key":"e_1_3_8_40_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.MR0618-226R"},{"key":"e_1_3_8_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1015286108"},{"key":"e_1_3_8_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12443"},{"key":"e_1_3_8_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/23287"},{"key":"e_1_3_8_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1049"},{"key":"e_1_3_8_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2011.02.009"},{"key":"e_1_3_8_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00012"},{"key":"e_1_3_8_47_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1602137"},{"key":"e_1_3_8_48_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201444688"},{"key":"e_1_3_8_49_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.10.6660"},{"key":"e_1_3_8_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601301"},{"key":"e_1_3_8_51_2","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.1700048"},{"key":"e_1_3_8_52_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.150.11.4822"},{"key":"e_1_3_8_53_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1801565"},{"key":"e_1_3_8_54_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-065X.1994.tb00894.x"},{"key":"e_1_3_8_55_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110308"},{"key":"e_1_3_8_56_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1440-1711.1998.00709.x"},{"key":"e_1_3_8_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90169-4"},{"key":"e_1_3_8_58_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.10.6934"},{"key":"e_1_3_8_59_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.1.40"},{"key":"e_1_3_8_60_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902115106"},{"key":"e_1_3_8_61_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101562"},{"key":"e_1_3_8_62_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077992"},{"key":"e_1_3_8_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077991"},{"key":"e_1_3_8_64_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01999"},{"key":"e_1_3_8_65_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900690"},{"key":"e_1_3_8_66_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900389"},{"key":"e_1_3_8_67_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10320-y"},{"key":"e_1_3_8_68_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20211112"},{"key":"e_1_3_8_69_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902490"},{"key":"e_1_3_8_70_2","doi-asserted-by":"publisher","DOI":"10.1186\/1746-1596-7-142"},{"key":"e_1_3_8_71_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10753-011-9417-2"},{"key":"e_1_3_8_72_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80681-0"},{"key":"e_1_3_8_73_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.6.3377"},{"key":"e_1_3_8_74_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.10.5931"},{"key":"e_1_3_8_75_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.10.6073"},{"key":"e_1_3_8_76_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1904096116"},{"key":"e_1_3_8_77_2","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2016.1249561"},{"key":"e_1_3_8_78_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40425-019-0744-4"},{"key":"e_1_3_8_79_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.681320"},{"key":"e_1_3_8_80_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201948309"},{"key":"e_1_3_8_81_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200775"},{"key":"e_1_3_8_82_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.9.5774"},{"key":"e_1_3_8_83_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.10.6649"},{"key":"e_1_3_8_84_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-100010"},{"key":"e_1_3_8_85_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-08-173658"},{"key":"e_1_3_8_86_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601884"},{"key":"e_1_3_8_87_2","first-page":"622","article-title":"Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study","volume":"60","author":"Miyazaki A","year":"1985","unstructured":"Miyazaki A, Hanafusa T, Yamada K, Miyagawa J, Fujino-Kurihara H, Nakajima H, Nonaka K, Tarui S. 1985 Predominance of T lymphocytes in pancreatic islets and spleen of pre-diabetic non-obese diabetic (NOD) mice: a longitudinal study. Clin. Exp. Immunol. 60, 622\u2013630.","journal-title":"Clin. Exp. Immunol."},{"key":"e_1_3_8_88_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1302273"},{"key":"e_1_3_8_89_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1445"},{"key":"e_1_3_8_90_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.5.2961"},{"key":"e_1_3_8_91_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1521-4141(199904)29:04<1243::AID-IMMU1243>3.0.CO;2-A"},{"key":"e_1_3_8_92_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80089-8"},{"key":"e_1_3_8_93_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.07.008"},{"key":"e_1_3_8_94_2","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.22139.1"},{"key":"e_1_3_8_95_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0145-305X(03)00027-2"},{"key":"e_1_3_8_96_2","doi-asserted-by":"publisher","DOI":"10.1159\/000019141"},{"key":"e_1_3_8_97_2","doi-asserted-by":"crossref","unstructured":"Adegoke A Thangavelu G Chou TF Petersen MI Kakugawa K May JF et al. 2024 Data from: Internal regulation between constitutively expressed T cell coinhibitory receptors BTLA and CD5 and tolerance in recent thymic emigrants. Figshare. (doi:10.6084\/m9.figshare.c.7492720)","DOI":"10.1101\/2024.01.10.574913"}],"container-title":["Open Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.240178","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/full-xml\/10.1098\/rsob.240178","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/royalsocietypublishing.org\/doi\/pdf\/10.1098\/rsob.240178","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T20:05:15Z","timestamp":1730232315000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/doi\/10.1098\/rsob.240178"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10]]},"references-count":96,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1098\/rsob.240178"],"URL":"https:\/\/doi.org\/10.1098\/rsob.240178","relation":{"has-review":[{"id-type":"doi","id":"10.1098\/RSOB.240178\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.240178\/v2\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.240178\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.240178\/v1\/review2","asserted-by":"object"},{"id-type":"doi","id":"10.1098\/RSOB.240178\/v1\/review1","asserted-by":"object"}],"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.01.10.574913","asserted-by":"object"}]},"ISSN":["2046-2441"],"issn-type":[{"value":"2046-2441","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10]]},"assertion":[{"value":"2024-06-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-23","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"240178"}}