{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:01:29Z","timestamp":1789671689103,"version":"4.0.1"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T00:00:00Z","timestamp":1638489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia\/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte\/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS\/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>). Flow cytometry of non-parenchymal liver cells obtained from CCl<jats:sub>4<\/jats:sub>-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8<jats:sup>+<\/jats:sup> T-lymphocytes and with an increase in ICOSL expression involving CD11b<jats:sup>high<\/jats:sup>\/F4-80<jats:sup>+<\/jats:sup> hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl<jats:sub>4<\/jats:sub>-treated ICOS knockout <jats:italic>(ICOS<jats:sup>-\/-<\/jats:sup><\/jats:italic>) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8<jats:sup>+<\/jats:sup> T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl<jats:sub>4<\/jats:sub>-treated <jats:italic>ICOS<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8<jats:sup>+<\/jats:sup> T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS\/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS\/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.<\/jats:p>","DOI":"10.3389\/fimmu.2021.786680","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T07:15:12Z","timestamp":1638515712000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":17,"title":["Inducible T-Cell Costimulator Mediates Lymphocyte\/Macrophage Interactions During Liver Repair"],"prefix":"10.3389","volume":"12","author":[{"given":"Naresh Naik","family":"Ramavath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila Lavanya","family":"Gadipudi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Provera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca 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