{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T11:53:21Z","timestamp":1781524401324,"version":"3.54.1"},"reference-count":69,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Interleukin-21 (IL-21) is a pleiotropic cytokine produced by CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells that critically regulates the differentiation and functions of various adaptive and innate immune cells. Emerging evidence suggests that IL-21 production increases in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells during aging. However, the long-term impact of sustained IL-21 exposure on peripheral tissues remains unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To address this question, we generated transgenic mice expressing a membrane-bound IL-21 isoform specifically in T cells (IL-21isoTg mice) and analyzed age-associated tissue alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Female IL-21isoTg mice developed progressive mammary gland dysplasia beginning at approximately 14 weeks of age, and more than 45% developed mammary tumors after 12 months. Comprehensive gene expression analysis of mammary epithelial cells (MECs) isolated prior to tumor onset (10 weeks of age) revealed robust upregulation of the\n                      <jats:italic>Spp1<\/jats:italic>\n                      gene encoding osteopontin (OPN) in IL-21isoTg mice. Quantitative RT-PCR confirmed a significant increase in\n                      <jats:italic>Spp1<\/jats:italic>\n                      expression in both MECs and mammary stromal cells of IL-21isoTg mice. Given the established role of OPN in shaping the tumor microenvironment (TME) and promoting immunosuppression, we investigated the mechanism underlying\n                      <jats:italic>Spp1<\/jats:italic>\n                      induction. Using splenocytes as a surrogate model for mammary stromal immune cells, we found that IL-21 stimulation selectively enhanced OPN expression in macrophages and B cells. In contrast, cytokines previously reported to induce\n                      <jats:italic>Spp1<\/jats:italic>\n                      , including IL-1\u03b2, IL-6, IL-17A, and TNF-\u03b1, failed to significantly upregulate\n                      <jats:italic>Spp1<\/jats:italic>\n                      in this context, indicating an IL-21-specific effect. Although IL-21 did not directly affect mammary epithelial tumor cell lines, it induced splenocyte-derived IL-6 and TNF-\u03b1, which subsequently promoted\n                      <jats:italic>Spp1<\/jats:italic>\n                      expression in tumor cell lines. These findings suggest that in IL-21isoTg mice, T cells accumulating in the mammary gland produce IL-21iso, which directly induces OPN expression in macrophages and B cells, and indirectly enhances OPN expression in MECs through IL-6 and TNF-\u03b1. Age-associated increases in IL-21 production may, therefore, promote mammary tumor development and progression by enhancing OPN expression, leading to local inflammation and immunosuppression within the mammary tissue.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1834095","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T13:10:08Z","timestamp":1780319408000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["IL-21 isoform transgenic mice spontaneously develop mammary tumors: possible involvement of IL-21-induced osteopontin expression in tumorigenesis"],"prefix":"10.3389","volume":"17","author":[{"given":"Risako","family":"Yamaguchi","sequence":"first","affiliation":[{"name":"Department of Immunology, Yamagata University Faculty of Medicine","place":["Yamagata, Japan"]},{"name":"Department of Obstetrics and Gynecology, Yamagata 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