{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T15:04:35Z","timestamp":1776006275288,"version":"3.50.1"},"reference-count":120,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T00:00:00Z","timestamp":1614729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI19\/00206"],"award-info":[{"award-number":["PI19\/00206"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","award":["GLD14\/00217"],"award-info":[{"award-number":["GLD14\/00217"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005564","name":"Gilead Sciences","doi-asserted-by":"publisher","award":["GLD16\/00014"],"award-info":[{"award-number":["GLD16\/00014"]}],"id":[{"id":"10.13039\/100005564","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Hepatitis C virus (HCV)-specific CD8+ T cell response is essential in natural HCV infection control, but it becomes exhausted during persistent infection. Nowadays, chronic HCV infection can be resolved by direct acting anti-viral treatment, but there are still some non-responders that could benefit from CD8+ T cell response restoration. To become fully reactive, T cell needs the complete release of T cell receptor (TCR) signalling but, during exhaustion this is blocked by the PD-1 effect on CD28 triggering. The T cell pool sensitive to PD-1 modulation is the progenitor subset but not the terminally differentiated effector population. Nevertheless, the blockade of PD-1\/PD-L1 checkpoint cannot be always enough to restore this pool. This is due to the HCV ability to impair other co-stimulatory mechanisms and metabolic pathways and to induce a pro-apoptotic state besides the TCR signalling impairment. In this sense, gamma-chain receptor cytokines involved in memory generation and maintenance, such as low-level IL-2, IL-7, IL-15, and IL-21, might carry out a positive effect on metabolic reprogramming, apoptosis blockade and restoration of co-stimulatory signalling. This review sheds light on the role of combinatory immunotherapeutic strategies to restore a reactive anti-HCV T cell response based on the mixture of PD-1 blocking plus IL-2\/IL-7\/IL-15\/IL-21 treatment.<\/jats:p>","DOI":"10.3390\/cells10030538","type":"journal-article","created":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T20:29:48Z","timestamp":1614803388000},"page":"538","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Gamma-Chain Receptor Cytokines &amp; PD-1 Manipulation to Restore HCV-Specific CD8+ T Cell Response during Chronic Hepatitis C"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4220-1287","authenticated-orcid":false,"given":"Julia","family":"Pe\u00f1a-Asensio","sequence":"first","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Department of Biology of Systems, University of Alcal\u00e1, E-28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henar","family":"Calvo","sequence":"additional","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Section of Gastroenterology &amp; Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miguel","family":"Torralba","sequence":"additional","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Service of Internal Medicine, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Department of Medicine &amp; Medical Specialties, University of Alcal\u00e1, E-28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaqu\u00edn","family":"Miquel","sequence":"additional","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Section of Gastroenterology &amp; Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eduardo","family":"Sanz-de-Villalobos","sequence":"additional","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Section of Gastroenterology &amp; Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6383-848X","authenticated-orcid":false,"given":"Juan-Ram\u00f3n","family":"Larrubia","sequence":"additional","affiliation":[{"name":"Translational Hepatology Unit, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Section of Gastroenterology &amp; Hepatology, Guadalajara University Hospital, E-19002 Guadalajara, Spain"},{"name":"Department of Medicine &amp; Medical Specialties, University of Alcal\u00e1, E-28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/nrgastro.2016.176","article-title":"Global epidemiology and burden of HCV infection and HCV-related disease","volume":"14","author":"Thrift","year":"2017","journal-title":"Nat. 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