Frontiers in immunology · 2026
Aberrant IL-21/STAT3 signaling disrupts regulatory T cell function and CD4+ T cell homeostasis in children with type 1 diabetes.
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Sun Xiaofeng, Zhao Jiou, Liu Jin, Zhou Wendi
Аннотация
BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by profound dysregulation of CD4+ 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-mediated autoimmunity; however, the immunoregulatory mechanisms linking IL-21 signaling to T cell imbalance in pediatric T1D remain incompletely understood.
METHODS: 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+ 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 in vitro. The immunological and pathological effects of STAT3 inhibition were further evaluated in a non-obese diabetic (NOD) mouse model.
RESULTS: Single-cell transcriptomic analysis revealed enhanced IL-21/STAT3 signaling activity in CD4+ 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+ T cell differentiation toward Th17 and Tfh phenotypes. Pharmacological inhibition of STAT3 effectively reversed IL-21-mediated Treg dysfunction and restored CD4+ T cell balance in vitro. In NOD mice, STAT3 inhibition ameliorated hyperglycemia, reduced pancreatic inflammation, preserved insulin-positive islets, and corrected systemic T cell subset imbalance.
CONCLUSION: Aberrant activation of the IL-21/STAT3 signaling axis may contribute to impaired Treg function and CD4+ T cell imbalance in pediatric T1D. These findings suggest that IL-21-STAT3-dependent immune dysregulation represents an important mechanism involved in T cell imbalance and autoimmune pathology in T1D.
METHODS: 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+ 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 in vitro. The immunological and pathological effects of STAT3 inhibition were further evaluated in a non-obese diabetic (NOD) mouse model.
RESULTS: Single-cell transcriptomic analysis revealed enhanced IL-21/STAT3 signaling activity in CD4+ 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+ T cell differentiation toward Th17 and Tfh phenotypes. Pharmacological inhibition of STAT3 effectively reversed IL-21-mediated Treg dysfunction and restored CD4+ T cell balance in vitro. In NOD mice, STAT3 inhibition ameliorated hyperglycemia, reduced pancreatic inflammation, preserved insulin-positive islets, and corrected systemic T cell subset imbalance.
CONCLUSION: Aberrant activation of the IL-21/STAT3 signaling axis may contribute to impaired Treg function and CD4+ T cell imbalance in pediatric T1D. These findings suggest that IL-21-STAT3-dependent immune dysregulation represents an important mechanism involved in T cell imbalance and autoimmune pathology in T1D.