{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:32:33Z","timestamp":1772029953207,"version":"3.50.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T00:00:00Z","timestamp":1717113600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T00:00:00Z","timestamp":1717113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["23K07786"],"award-info":[{"award-number":["23K07786"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["23K07786"],"award-info":[{"award-number":["23K07786"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["23K07786"],"award-info":[{"award-number":["23K07786"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Adult T-cell leukemia\/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup> phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13<jats:sup>+<\/jats:sup> Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13<jats:sup>\u2212<\/jats:sup> (designated as MT-50.1) and CD13<jats:sup>+<\/jats:sup> (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-\u03b2, expressed higher levels of Foxp3, and showed stronger suppression of CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>\u2212<\/jats:sup> T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> HTLV-1-infected cells.<\/jats:p>","DOI":"10.1038\/s41598-024-63494-x","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T14:04:23Z","timestamp":1717164263000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel paired CD13-negative (MT-50.1) and CD13-positive (MT-50.4) HTLV-1-infected T-cell lines with differential regulatory T cell-like activity"],"prefix":"10.1038","volume":"14","author":[{"given":"Yuki","family":"Egawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomonori","family":"Higuchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumiko","family":"Hashida","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuyuki","family":"Ueno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Daibata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,5,31]]},"reference":[{"key":"63494_CR1","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1182\/blood.V50.3.481.481","volume":"50","author":"T Uchiyama","year":"1977","unstructured":"Uchiyama, T., Yodoi, J., Sagawa, K., Takatsuki, K. & Uchino, H. Adult T-cell leukemia: Clinical and hematologic features of 16 cases. Blood 50, 481\u2013492. https:\/\/doi.org\/10.1182\/blood.V50.3.481.481 (1977).","journal-title":"Blood"},{"key":"63494_CR2","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/294770a0","volume":"294","author":"I Miyoshi","year":"1981","unstructured":"Miyoshi, I. et al. Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294, 770\u2013771. https:\/\/doi.org\/10.1038\/294770a0 (1981).","journal-title":"Nature"},{"key":"63494_CR3","doi-asserted-by":"publisher","first-page":"e539","DOI":"10.1016\/S2352-3026(23)00087-X","volume":"10","author":"JS O'Donnell","year":"2023","unstructured":"O\u2019Donnell, J. S., Hunt, S. K. & Chappell, K. J. Integrated molecular and immunological features of human T-lymphotropic virus type 1 infection and disease progression to adult T-cell leukaemia or lymphoma. Lancet Haematol. 10, e539\u2013e548. https:\/\/doi.org\/10.1016\/S2352-3026(23)00087-X (2023).","journal-title":"Lancet Haematol."},{"key":"63494_CR4","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1097\/01.tp.0000235186.30113.c7","volume":"82","author":"N Kawano","year":"2006","unstructured":"Kawano, N. et al. Adult T-cell leukemia development from a human T-cell leukemia virus type I carrier after a living-donor liver transplantation. Transplantation 82, 840\u2013843. https:\/\/doi.org\/10.1097\/01.tp.0000235186.30113.c7 (2006).","journal-title":"Transplantation"},{"key":"63494_CR5","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1111\/j.1365-2141.2004.04999.x","volume":"126","author":"K Karube","year":"2004","unstructured":"Karube, K. et al. Expression of FoxP3, a key molecule in CD4+CD25+ regulatory T cells, in adult T-cell leukaemia\/lymphoma cells. Br. J. Haematol. 126, 81\u201384. https:\/\/doi.org\/10.1111\/j.1365-2141.2004.04999.x (2004).","journal-title":"Br. J. Haematol."},{"key":"63494_CR6","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1038\/modpathol.2008.25","volume":"21","author":"K Karube","year":"2008","unstructured":"Karube, K. et al. The relationship of FOXP3 expression and clinicopathological characteristics in adult T-cell leukemia\/lymphoma. Mod. Pathol. 21, 617\u2013625. https:\/\/doi.org\/10.1038\/modpathol.2008.25 (2008).","journal-title":"Mod. Pathol."},{"key":"63494_CR7","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/1742-4690-9-46","volume":"9","author":"Y Satou","year":"2012","unstructured":"Satou, Y. et al. HTLV-1 modulates the frequency and phenotype of FoxP3+CD4+ T cells in virus-infected individuals. Retrovirology 9, 46. https:\/\/doi.org\/10.1186\/1742-4690-9-46 (2012).","journal-title":"Retrovirology"},{"key":"63494_CR8","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.micinf.2004.02.020","volume":"6","author":"S Hori","year":"2004","unstructured":"Hori, S. & Sakaguchi, S. Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect. 6, 745\u2013751. https:\/\/doi.org\/10.1016\/j.micinf.2004.02.020 (2004).","journal-title":"Microbes Infect."},{"key":"63494_CR9","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nri2343","volume":"8","author":"DAA Vignali","year":"2008","unstructured":"Vignali, D. A. A., Collison, L. W. & Workman, C. J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523\u2013532. https:\/\/doi.org\/10.1038\/nri2343 (2008).","journal-title":"Nat. Rev. Immunol."},{"key":"63494_CR10","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1111\/j.1349-7006.2005.00080.x","volume":"96","author":"T Kohno","year":"2005","unstructured":"Kohno, T. et al. Possible origin of adult T-cell leukemia\/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells. Cancer Sci. 96, 527\u2013533. https:\/\/doi.org\/10.1111\/j.1349-7006.2005.00080.x (2005).","journal-title":"Cancer Sci."},{"key":"63494_CR11","doi-asserted-by":"publisher","first-page":"2052","DOI":"10.1002\/ijc.22536","volume":"120","author":"H Yano","year":"2007","unstructured":"Yano, H. et al. Regulatory T-cell function of adult T-cell leukemia\/lymphoma cells. Int. J. Cancer 120, 2052\u20132057. https:\/\/doi.org\/10.1002\/ijc.22536 (2007).","journal-title":"Int. J. Cancer"},{"key":"63494_CR12","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1093\/intimm\/dxh366","volume":"18","author":"S Chen","year":"2006","unstructured":"Chen, S. et al. Regulatory T cell-like activity of Foxp3+ adult T cell leukemia cells. Int. Immunol. 18, 269\u2013277. https:\/\/doi.org\/10.1093\/intimm\/dxh366 (2006).","journal-title":"Int. Immunol."},{"key":"63494_CR13","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1111\/j.1349-7006.2007.00646.x","volume":"99","author":"T Shimauchi","year":"2008","unstructured":"Shimauchi, T., Kabashima, K. & Tokura, Y. Adult T-cell leukemia\/lymphoma cells from blood and skin tumors express cytotoxic T lymphocyte-associated antigen-4 and Foxp3 but lack suppressor activity toward autologous CD8+ T cells. Cancer Sci. 99, 98\u2013106. https:\/\/doi.org\/10.1111\/j.1349-7006.2007.00646.x (2008).","journal-title":"Cancer Sci."},{"key":"63494_CR14","doi-asserted-by":"publisher","first-page":"2375","DOI":"10.1002\/ijc.24664","volume":"125","author":"F Toulza","year":"2009","unstructured":"Toulza, F. et al. FoxP3+ regulatory T cells are distinct from leukemia cells in HTLV-1-associated adult T-cell leukemia. Int. J. Cancer 125, 2375\u20132382. https:\/\/doi.org\/10.1002\/ijc.24664 (2009).","journal-title":"Int. J. Cancer"},{"key":"63494_CR15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/s0167-5699(98)01398-x","volume":"20","author":"D Riemann","year":"1999","unstructured":"Riemann, D., Kehlen, A. & Langner, J. CD13\u2013not just a marker in leukemia typing. Immunol. Today 20, 83\u201388. https:\/\/doi.org\/10.1016\/s0167-5699(98)01398-x (1999).","journal-title":"Immunol. Today"},{"key":"63494_CR16","doi-asserted-by":"publisher","first-page":"2578","DOI":"10.4161\/cc.8.16.9302","volume":"8","author":"S Ju","year":"2009","unstructured":"Ju, S. et al. CD13+CD4+CD25hi regulatory T cells exhibit higher suppressive function and increase with tumor stage in non-small cell lung cancer patients. Cell Cycle 8, 2578\u20132585. https:\/\/doi.org\/10.4161\/cc.8.16.9302 (2009).","journal-title":"Cell Cycle"},{"key":"63494_CR17","doi-asserted-by":"publisher","first-page":"2191","DOI":"10.1084\/jem.169.6.2191","volume":"169","author":"I Saito","year":"1989","unstructured":"Saito, I., Servenius, B., Compton, T. & Fox, R. I. Detection of Epstein-Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patients with Sjogren\u2019s syndrome. J. Exp. Med. 169, 2191\u20132198. https:\/\/doi.org\/10.1084\/jem.169.6.2191 (1989).","journal-title":"J. Exp. Med."},{"key":"63494_CR18","doi-asserted-by":"publisher","unstructured":"Miyoshi, I. et al. A novel T-cell line derived from adult T-cell leukemia. Gan 71, 155\u2013156; https:\/\/doi.org\/10.20772\/cancersci1959.71.1_155 (1980).","DOI":"10.20772\/cancersci1959.71.1_155"},{"key":"63494_CR19","doi-asserted-by":"publisher","first-page":"6061","DOI":"10.1073\/pnas.80.19.6061","volume":"80","author":"H Hoshino","year":"1983","unstructured":"Hoshino, H. et al. Establishment and characterization of 10 cell lines derived from patients with adult T-cell leukemia. Proc. Natl. Acad. Sci. USA 80, 6061\u20136065. https:\/\/doi.org\/10.1073\/pnas.80.19.6061 (1983).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"63494_CR20","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1084\/jem.189.7.1063","volume":"189","author":"T Maeda","year":"1999","unstructured":"Maeda, T. et al. Fas gene mutation in the progression of adult T cell leukemia. J. Exp. Med. 189, 1063\u20131071. https:\/\/doi.org\/10.1084\/jem.189.7.1063 (1999).","journal-title":"J. Exp. Med."},{"key":"63494_CR21","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/s0145-2126(01)00169-2","volume":"26","author":"Y Liu","year":"2002","unstructured":"Liu, Y. et al. Engraftment and tumorigenesis of HTLV-1 transformed T cell lines in SCID\/bg and NOD\/SCID mice. Leuk. Res. 26, 561\u2013567. https:\/\/doi.org\/10.1016\/s0145-2126(01)00169-2 (2002).","journal-title":"Leuk. Res."},{"key":"63494_CR22","doi-asserted-by":"publisher","first-page":"356","DOI":"10.3389\/fmicb.2020.00356","volume":"11","author":"M Maeda","year":"2020","unstructured":"Maeda, M. et al. IL-2\/IL-2 receptor pathway plays a crucial role in the growth and malignant transformation of HTLV-1-infected T cells to develop adult T-cell leukemia. Front. Microbiol. 11, 356. https:\/\/doi.org\/10.3389\/fmicb.2020.00356 (2020).","journal-title":"Front. Microbiol."},{"key":"63494_CR23","first-page":"686","volume":"16","author":"KA LaGree","year":"1988","unstructured":"LaGree, K. A., Lee, A. T., Stetten, G. & Strauss, P. R. The human Jurkat (FHCRC-11) cell line is heterogeneous in ploidy and cell size and releases detergent-soluble DNA. Exp. Hematol. 16, 686\u2013690 (1988).","journal-title":"Exp. Hematol."},{"key":"63494_CR24","doi-asserted-by":"publisher","first-page":"2534","DOI":"10.1073\/pnas.81.8.2534","volume":"81","author":"M Yoshida","year":"1984","unstructured":"Yoshida, M., Seiki, M., Yamaguchi, K. & Takatsuki, K. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc. Natl. Acad. Sci. USA 81, 2534\u20132537. https:\/\/doi.org\/10.1073\/pnas.81.8.2534 (1984).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"63494_CR25","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1016\/s0140-6736(71)90287-x","volume":"2","author":"M Seabright","year":"1971","unstructured":"Seabright, M. A rapid banding technique for human chromosomes. Lancet 2, 971\u2013972. https:\/\/doi.org\/10.1016\/s0140-6736(71)90287-x (1971).","journal-title":"Lancet"},{"key":"63494_CR26","doi-asserted-by":"publisher","unstructured":"Tanabe, H. et al. Cell line individualization by STR multiplex system in the cell bank found cross-contamination between ECV304 and EJ-1\/T24. Tiss. Cult. Res. Commun. 18, 329\u2013338; https:\/\/doi.org\/10.11418\/jtca1981.18.4_329 (1999).","DOI":"10.11418\/jtca1981.18.4_329"},{"key":"63494_CR27","doi-asserted-by":"publisher","first-page":"1701","DOI":"10.1084\/jem.20060772","volume":"203","author":"W Liu","year":"2006","unstructured":"Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701\u20131711. https:\/\/doi.org\/10.1084\/jem.20060772 (2006).","journal-title":"J. Exp. Med."},{"key":"63494_CR28","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1038\/sj.leu.2401388","volume":"13","author":"K Sekine","year":"1999","unstructured":"Sekine, K., Fujii, H. & Abe, F. Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines. Leukemia 13, 729\u2013734. https:\/\/doi.org\/10.1038\/sj.leu.2401388 (1999).","journal-title":"Leukemia"},{"key":"63494_CR29","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1038\/cmi.2014.123","volume":"12","author":"R Hamano","year":"2015","unstructured":"Hamano, R., Wu, X., Wang, Y., Oppenheim, J. J. & Chen, X. Characterization of MT-2 cells as a human regulatory T cell-like cell line. Cell Mol. Immunol. 12, 780\u2013782. https:\/\/doi.org\/10.1038\/cmi.2014.123 (2015).","journal-title":"Cell Mol. Immunol."},{"key":"63494_CR30","doi-asserted-by":"publisher","first-page":"7529","DOI":"10.1158\/1078-0432.CCR-04-0983","volume":"10","author":"T Ishida","year":"2004","unstructured":"Ishida, T. et al. The CC chemokine receptor 4 as a novel specific molecular target for immunotherapy in adult T-cell leukemia\/lymphoma. Clin. Cancer Res. 10, 7529\u20137539. https:\/\/doi.org\/10.1158\/1078-0432.CCR-04-0983 (2004).","journal-title":"Clin. Cancer Res."},{"key":"63494_CR31","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1038\/cmi.2015.44","volume":"12","author":"H Zeng","year":"2015","unstructured":"Zeng, H., Zhang, R., Jin, B. & Chen, L. Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol. Immunol. 12, 566\u2013571. https:\/\/doi.org\/10.1038\/cmi.2015.44 (2015).","journal-title":"Cell Mol. Immunol."},{"key":"63494_CR32","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/icb.2013.12","volume":"91","author":"A Banerjee","year":"2013","unstructured":"Banerjee, A., Vasanthakumar, A. & Grigoriadis, G. Modulating T regulatory cells in cancer: How close are we?. Immunol. Cell Biol. 91, 340\u2013349. https:\/\/doi.org\/10.1038\/icb.2013.12 (2013).","journal-title":"Immunol. Cell Biol."},{"key":"63494_CR33","doi-asserted-by":"publisher","first-page":"1397","DOI":"10.4049\/jimmunol.1701703","volume":"202","author":"S Chellappa","year":"2019","unstructured":"Chellappa, S. et al. The PI3K p110\u03b4 isoform inhibitor idelalisib preferentially inhibits human regulatory T cell function. J. Immunol. 202, 1397\u20131405. https:\/\/doi.org\/10.4049\/jimmunol.1701703 (2019).","journal-title":"J. Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63494-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63494-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63494-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T14:07:27Z","timestamp":1717164447000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-024-63494-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,31]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["63494"],"URL":"https:\/\/doi.org\/10.1038\/s41598-024-63494-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,31]]},"assertion":[{"value":"13 February 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 May 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12549"}}