{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T06:08:04Z","timestamp":1779084484530,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"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>Background<\/jats:title>\n                    <jats:p>\n                      Type 1 diabetes (T1D) is an autoimmune disease characterized by profound dysregulation of CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell subsets, particularly impaired regulatory T cell (Treg) function accompanied by excessive Th17 and T follicular helper (Tfh) cell responses. Interleukin-21 (IL-21) has been implicated in T cell\u2013mediated autoimmunity; however, the immunoregulatory mechanisms linking IL-21 signaling to T cell imbalance in pediatric T1D remain incompletely understood.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Single-cell RNA sequencing data from children with T1D were analyzed to characterize IL-21\/STAT3 pathway activity across immune cell subsets. Functional assays were performed using primary human CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells and Tregs treated with IL-21 and the STAT3 inhibitor Stattic. T cell differentiation, suppressive function, cytokine production, and STAT3 activation were assessed\n                      <jats:italic>in vitro<\/jats:italic>\n                      . The immunological and pathological effects of STAT3 inhibition were further evaluated in a non-obese diabetic (NOD) mouse model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Single-cell transcriptomic analysis revealed enhanced IL-21\/STAT3 signaling activity in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell populations from children with T1D. IL-21 stimulation induced STAT3 phosphorylation and nuclear translocation, leading to reduced FoxP3 expression, impaired Treg-associated suppressive function, and a shift in CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell differentiation toward Th17 and Tfh phenotypes. Pharmacological inhibition of STAT3 effectively reversed IL-21\u2013mediated Treg dysfunction and restored CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell balance\n                      <jats:italic>in vitro<\/jats:italic>\n                      . In NOD mice, STAT3 inhibition ameliorated hyperglycemia, reduced pancreatic inflammation, preserved insulin-positive islets, and corrected systemic T cell subset imbalance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Aberrant activation of the IL-21\/STAT3 signaling axis may contribute to impaired Treg function and CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cell imbalance in pediatric T1D. These findings suggest that IL-21\u2013STAT3\u2013dependent immune dysregulation represents an important mechanism involved in T cell imbalance and autoimmune pathology in T1D.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1791993","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:44:33Z","timestamp":1779083073000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Aberrant IL-21\/STAT3 signaling disrupts regulatory T cell function and CD4+ T cell homeostasis in children with type 1 diabetes"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaofeng","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Pediatrics, The Affiliated Huaian No.1 People\u2019s Hospital of Nanjing Medical University","place":["Huaian, Jiangsu, 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