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Previous studies have demonstrated that T cells of BLV-infected cattle show increased expression of immune checkpoint molecules, including programmed death-1 (PD-1), lymphocyte-activation gene-3 (LAG-3), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and T-cell immunoglobulin domain and mucin domain-3 (TIM-3), leading to T-cell exhaustion. However, the key immune checkpoint molecules driving T-cell exhaustion in BLV-induced tumorigenesis remained unclear. In this study, we identified the key immune checkpoint molecules by performing comprehensive flow cytometric analyses of T cells from EBL cattle, and elucidated the phenotype and function of exhausted T cells using a transcriptomic analysis by RNA sequencing and cell culture assays. The comprehensive expression analysis revealed that the proportion of CD4+ and CD8+ T cells co-expressing PD-1 and TIM-3 was significantly increased in the peripheral blood and tumor tissues of EBL cattle compared to healthy cattle. Transcriptomic analysis of PD-1+TIM-3+ T cells revealed the upregulation of genes related to terminal exhaustion and the downregulation of genes related to T-cell differentiation and response in this subset. Additionally, PD-1+TIM-3+ T cells exhibited higher expression of CTLA-4, LAG-3, and Eomes, and lower expression of T-bet, suggesting a terminally exhausted phenotype. Cell culture assays revealed a significant impairment in IFN-\u03b3 production in PD-1+TIM-3+ T cells upon stimulation, reflecting severe dysfunction. These findings indicate that PD-1+TIM-3+ T cells play a central role in T-cell exhaustion during BLV-induced tumorigenesis. This study provides valuable insights for future therapeutic strategies against BLV infection.<\/jats:p>","DOI":"10.1093\/jimmun\/vkaf050","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:42:53Z","timestamp":1748306573000},"page":"2600-2616","source":"Crossref","is-referenced-by-count":8,"title":["Comprehensive analysis of immune checkpoint molecules profiles phenotype and function of exhausted T cells in enzootic bovine leukosis"],"prefix":"10.1093","volume":"214","author":[{"given":"Hayato","family":"Nakamura","sequence":"first","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["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,","place":["Japan"]},{"name":"Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Veterinary Research Unit, International Institute for Zoonosis Control, Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Okagawa","sequence":"additional","affiliation":[{"name":"Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoya","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wisa","family":"Tiyamanee","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["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,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koume","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Watari","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Kamitani","sequence":"additional","affiliation":[{"name":"Hokkaido Hayakita Meat Inspection Center, Hokkaido Government , Abira,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Saito","sequence":"additional","affiliation":[{"name":"Hokkaido Hayakita Meat Inspection Center, Hokkaido Government , Abira,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukinari","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine , Sendai,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1313-1494","authenticated-orcid":false,"given":"Yasuhiko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Institute for Vaccine Research and Development (HU-IVReD), Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University , Sapporo,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Murata","sequence":"additional","affiliation":[{"name":"Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University , Sapporo,","place":["Japan"]},{"name":"Veterinary Research Unit, International Institute for Zoonosis Control, Hokkaido University , 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