{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T09:50:41Z","timestamp":1767865841153,"version":"3.49.0"},"reference-count":48,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunology"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In severe respiratory virus infections, including influenza, an exaggerated host immune response has been linked to the severe disease and death. Control of the overwhelming immune response is thus essential. Efforts with broad\u2010spectrum immunosuppressive agents such as steroids are disappointing. A better understanding of host immune response using animal experimental system is required to avoid undesired outcome of experimental manipulation. Following severe influenza virus infection in influenza hemagglutinin antigen\u2010specific transgenic mouse experimental model, step\u2010wise evolving cells from a pool of na\u00efve hemagglutinin\u2010specific CD4<jats:sup>+<\/jats:sup> T cells were studied for phenotypic, genomic, and functional characterization <jats:italic>in vivo<\/jats:italic>. Na\u00efve CD4<jats:sup>+<\/jats:sup> T cells respond with Th1 commitment in the absolute majority. They first develop into LAG\u20103<jats:sup>Med<\/jats:sup>IFN\u2010\u03b3\u2010secreting Th1 effectors and then evolve into LAG\u20103<jats:sup>High<\/jats:sup>IFN\u2010\u03b3\u2010not\u2010secreting regulators with increasing LAG\u20103 expression upon continuous activation and cell division. The LAG\u20103<jats:sup>Med<\/jats:sup>IFN\u2010\u03b3\u2010secreting effectors contribute to inflammation, boost inflammatory response of cognate antigen\u2010specific CD8<jats:sup>+<\/jats:sup> T cells, and aggravate the disease despite facilitated virus clearance. In contrast, LAG\u20103<jats:sup>High<\/jats:sup> regulators do not contribute to inflammation, suppress CD8<jats:sup>+<\/jats:sup> T cell inflammatory response, alleviate lung pathology, and ameliorate the disease with preserved virus clearance. Moderated CD8<jats:sup>+<\/jats:sup> T cells retain proliferative capacity, and persist beyond virus clearance. Such moderation is distinct from Foxp\u20103<jats:sup>+<\/jats:sup> regulator\u2010mediated suppression, which suppresses proliferative and inflammatory responses of the CD8<jats:sup>+<\/jats:sup> T cells and impairs virus clearance with inflammation alleviation. Origin of regulatory from the effector cells of LAG\u20103\u2010marked Th1 immunity alleviates lung inflammation without impairment of virus eradication.<\/jats:p>","DOI":"10.1111\/imm.13620","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T03:24:15Z","timestamp":1671161055000},"page":"167-184","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The origin of regulatory from the effector cells in LAG\u20103\u2010marked Th1 immunity against severe influenza virus infection"],"prefix":"10.1111","volume":"169","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5372-629X","authenticated-orcid":false,"given":"Avijit","family":"Dutta","sequence":"first","affiliation":[{"name":"Research Center for Emerging Viral Infections, College of Medicine Chang Gung University  Taoyuan Taiwan"},{"name":"Division of Infectious Diseases, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen\u2010Yiu","family":"Hung","sequence":"additional","affiliation":[{"name":"Division of Thoracic Medicine, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tse\u2010Ching","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pathology Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"},{"name":"College of Medicine Chang Gung University, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chia\u2010Shiang","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung\u2010Han","family":"Hsiao","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yung\u2010Chang","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Medicine Chang Gung University, Guishan  Taoyuan City Taiwan"},{"name":"Division of Hematology and Oncology, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun\u2010Yen","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Medicine Chang Gung University, Guishan  Taoyuan City Taiwan"},{"name":"Division of Hepatogastroenterology, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ching\u2010Tai","family":"Huang","sequence":"additional","affiliation":[{"name":"Research Center for Emerging Viral Infections, College of Medicine Chang Gung University  Taoyuan Taiwan"},{"name":"Division of Infectious Diseases, Department of Medicine Chang Gung Memorial Hospital, Guishan  Taoyuan City Taiwan"},{"name":"College of Medicine Chang Gung University, Guishan  Taoyuan City Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2026131"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-019-2395-8"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0030343"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201706-1172OC"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021436"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30317-2"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa601"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200320274"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-018-0004-9"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri1032"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.3.1080"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.26.021607.090331"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2004.08.010"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.05.001"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1205894109"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1202434"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms7374"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep32973"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-04365-6"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2019.152904"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2100020"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1103336"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80702-3"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12519"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0367"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200323382"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.171.5.1393"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200208)32:8<2255::AID-IMMU2255>3.0.CO;2-A"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2389"},{"key":"e_1_2_10_31_1","article-title":"The role of Foxp3 and Tbet co\u2010expressing Treg cells in lung carcinoma","volume":"7","author":"Kachler K","year":"2018","journal-title":"Onco Targets Ther"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7520605"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI130426"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2017.22"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.019"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.genrep.2018.05.006"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.8.4590"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms1272"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1172702"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.05685-11"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22147522"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203302"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4495"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004315"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/imcb.12492"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-virology-031413-085537"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1174182"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri778"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20050227"}],"container-title":["Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13620","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/imm.13620","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/imm.13620","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,20]],"date-time":"2023-08-20T19:52:52Z","timestamp":1692561172000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/imm.13620"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,23]]},"references-count":48,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,6]]}},"alternative-id":["10.1111\/imm.13620"],"URL":"https:\/\/doi.org\/10.1111\/imm.13620","archive":["Portico"],"relation":{},"ISSN":["0019-2805","1365-2567"],"issn-type":[{"value":"0019-2805","type":"print"},{"value":"1365-2567","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,23]]},"assertion":[{"value":"2022-09-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-11","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}