{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:16:11Z","timestamp":1789690571257,"version":"4.0.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012615","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI70725"],"award-info":[{"award-number":["R01AI70725"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005347","name":"American Association for the Study of Liver Diseases","doi-asserted-by":"publisher","award":["Pinnacle Research Award"],"award-info":[{"award-number":["Pinnacle Research Award"]}],"id":[{"id":"10.13039\/100005347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5T32GM007491"],"award-info":[{"award-number":["5T32GM007491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI170725-03S1"],"award-info":[{"award-number":["R01AI170725-03S1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH Cancer Center","award":["P30CA013330"],"award-info":[{"award-number":["P30CA013330"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>In hepatitis C virus (HCV) infection, CD4+ and CD8+ T cells are crucial for viral control. However, a detailed understanding of the kinetic of CD4+ T cell help and its role in the generation of different CD8+ T cell subsets during acute infection is lacking. The absence of a small HCV animal model has impeded mechanistic studies of hepatic antiviral T cell immunity and HCV vaccine development. In this study, we used a recently developed HCV-related rodent hepacivirus infection mouse model to investigate the impact of CD4+ T cell help on the hepatic CD8+ T cell response and viral clearance during hepacivirus infection in vivo. Our results revealed a specific kinetic of CD4+ T cell dependency during acute infection. Early CD4+ T cell help was essential for CD8+ T cell priming and viral clearance, while CD4+ T cells became dispensable during later stages of acute infection. Effector CD8+ T cells directly mediated timely hepacivirus clearance. An analysis of hepatic CD8+ T cells specific for two different viral epitopes revealed the induction of subsets of liver-homing CD103+CD49a+ and CD103-CD49a+ effector CD8+ T cells with elevated IFN-\u03b3 and TNF-\u03b1 production. CD103+CD49a+ T cells further persisted as tissue-resident memory subsets. A lack of CD4+ T cell help and CD40L-CD40 interactions resulted in reduced effector functions and phenotypical changes in effector CD8+ T cells and a specific loss of the CD103+CD49a+ subset. In summary, our study shows that early CD4+ T cell help through CD40L signaling is essential for priming functional effector CD8+ T cell subsets, including unique liver-homing subsets, and hepacivirus clearance.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012615","type":"journal-article","created":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T17:32:41Z","timestamp":1728667961000},"page":"e1012615","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["CD4+ T cell help during early acute hepacivirus infection is critical for viral clearance and the generation of a liver-homing CD103+CD49a+ effector CD8+ T cell subset"],"prefix":"10.1371","volume":"20","author":[{"given":"Jarrett","family":"Lopez-Scarim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustyn","family":"Mendoza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shashank M.","family":"Nambiar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0477-1748","authenticated-orcid":true,"given":"Eva","family":"Billerbeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"issue":"8","key":"ppat.1012615.ref001","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1038\/s41575-022-00608-8","article-title":"Breakthroughs in hepatitis C research: from discovery to cure.","volume":"19","author":"MP Manns","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"10407","key":"ppat.1012615.ref002","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0140-6736(23)01320-X","article-title":"Hepatitis C.","volume":"402","author":"M Martinello","year":"2023","journal-title":"Lancet"},{"issue":"2","key":"ppat.1012615.ref003","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41575-021-00570-x","article-title":"Vaccination at the forefront of the fight against hepatitis B and C.","volume":"19","author":"MH El-Sayed","year":"2022","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"6","key":"ppat.1012615.ref004","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1056\/NEJMoa2023345","article-title":"Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection","volume":"384","author":"K Page","year":"2021","journal-title":"N Engl J Med"},{"key":"ppat.1012615.ref005","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.coviro.2021.08.011","article-title":"T cell responses during HBV and HCV infections: similar but not quite the same?","volume":"51","author":"NH Shoukry","year":"2021","journal-title":"Curr Opin Virol."},{"key":"ppat.1012615.ref006","article-title":"T cell immunity to hepatitis C virus: lessons for a prophylactic HCV vaccine","author":"R. 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