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Hospital","award":["JP24K01918"],"award-info":[{"award-number":["JP24K01918"]}]},{"name":"Hokkaido University Veterinary Teaching Hospital","award":["JP223fa627005"],"award-info":[{"award-number":["JP223fa627005"]}]},{"name":"Hokkaido University Veterinary Teaching Hospital","award":["JP25ama121008"],"award-info":[{"award-number":["JP25ama121008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Veterinary Sciences"],"abstract":"<jats:p>Bovine leukemia virus (BLV) infects B cells in ruminants and causes lymphoma after an extended latency period. Previous studies have demonstrated T-cell exhaustion through the upregulation of immunoinhibitory molecules, including programmed death-ligand 1 (PD-L1) and T-cell immunoglobulin and mucin domain-3 (TIM-3), in BLV-infected cattle. However, studying T-cell exhaustion across all BLV infection stages remains challenging due to the virus\u2019s prolonged latency in cattle. Sheep provide a valuable model, as they develop lymphoma more rapidly than cattle. This study examined PD-L1 and TIM-3 expression kinetics and T-cell function in BLV-infected sheep. During persistent infection, PD-L1 expression was correlated with BLV proviral load. TIM-3 expression increased in CD4+, CD8+, and \u03b3\u03b4TCR+ T cells. Functional analysis revealed that TIM-3 blockade enhanced T-cell activation markers (CD25 and CD69) in cultured PBMCs from infected sheep and increased CD69+IFN-\u03b3+ and CD69+TNF-\u03b1+ populations, particularly among CD4+ T cells. Combined PD-L1 and TIM-3 blockade significantly enhanced cytokine production in both CD4+ and CD8+ T cells, while PD-L1 blockade alone showed limited effects. These findings demonstrate the effect of TIM-3 blockade in restoring immune function during chronic BLV infection, effective both alone and in combination. This study validates sheep as a valuable model for investigating immune checkpoint dynamics and evaluating immunotherapies for BLV infection and other chronic diseases.<\/jats:p>","DOI":"10.3390\/vetsci12090810","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T14:43:18Z","timestamp":1756219398000},"page":"810","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Evaluation of PD-L1 and TIM-3 Pathways in T Cells During Experimental Bovine Leukemia Virus Infection in Sheep"],"prefix":"10.3390","volume":"12","author":[{"given":"Wisa","family":"Tiyamanee","sequence":"first","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1391-9732","authenticated-orcid":false,"given":"Tomohiro","family":"Okagawa","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan"},{"name":"Business Development Unit, FASMAC Co., Ltd., Atsugi 243-0021, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4904-7590","authenticated-orcid":false,"given":"Shinji","family":"Yamada","sequence":"additional","affiliation":[{"name":"Cooperative Department of Veterinary Medicine, Faculty of Veterinary Medicine, Iwate University, Morioka 020-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Ikehata","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, 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Japan"},{"name":"International Affairs Office, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3813-818X","authenticated-orcid":false,"given":"Kenji","family":"Murakami","sequence":"additional","affiliation":[{"name":"Cooperative Department of Veterinary Medicine, Faculty of Veterinary Medicine, Iwate University, Morioka 020-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Konnai","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 060-0818, Japan"},{"name":"Veterinary Research Unit, International Institute of Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan"},{"name":"Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University, Sapporo 001-0021, Japan"},{"name":"One Health Research Center, Hokkaido University, Sapporo 060-0818, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1084\/jem.188.12.2205","article-title":"Viral immune evasion due to persistence of activated T cells without effector function","volume":"188","author":"Zajac","year":"1998","journal-title":"J. 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