Reversing Dysfunction of CCR9⁺ Regulatory T Cells by Targeting the IL-21/IL-17 Axis Improves Type 1 Diabetes.

Authors

Yulian Xia, Qing He, Yuhui Yao, Lei Yang, Shanshan Zhan, Shunfeng Mao

Published in

Diabetes, metabolic syndrome and obesity : targets and therapy. Volume 19. Pages 605204. Epub Aug 30, 2026.

Abstract

The functional status of regulatory T cells expressing the gut-homing receptor CCR9 (CCR9⁺ Tregs) in type 1 diabetes mellitus (T1DM) remains unclear. This study aims to investigate the functional alterations of CCR9⁺ Tregs in a T1DM model and evaluate the interventional effect of targeting the IL-21/IL-17 axis on their dysfunction.
The spontaneous T1DM non-obese diabetic (NOD) mouse model was employed. CCR9⁺ and CCR9^- Treg subsets were isolated from the spleen by flow cytometry. Their in vitro suppressive capacity on effector T cell (Teff) proliferation was assayed, and cytokine expression was analyzed using flow cytometry and qPCR. In vitro, CCR9⁺ Tregs were treated with different concentrations (50 and 100 ng/mL) of the anti-IL-21 monoclonal antibody (Avizakimab) to assess its effects on IL-21/IL-17A secretion and immunosuppressive function. In vivo, T1DM NOD mice were randomly assigned to a saline control group (n=3) and an Avizakimab treatment group (n=3, 10 mg/kg, tail vein injection, every other day for 2 weeks). Fasting blood glucose levels were monitored, pancreatic insulitis and pathological damage were evaluated by H&E staining, and the proportion of peripheral blood IL-17A⁺ cells was analyzed by flow cytometry.
Compared to CCR9^- Tregs, CCR9⁺ Tregs exhibited a significantly reduced ability to suppress Teff proliferation, secreted less of the anti-inflammatory cytokine IL-10, and showed significantly upregulated expression of the pro-inflammatory cytokines IL-17A and IL-21. Avizakimab effectively and dose-dependently inhibited the abnormal secretion of IL-21 and IL-17A by CCR9⁺ Tregs in vitro and restored their suppressive function on Teff proliferation. In vivo, Avizakimab treatment significantly lowered fasting blood glucose levels in T1DM NOD mice, alleviated pancreatic insulitis and pathological damage, and downregulated the proportion of IL-17A⁺ cells in peripheral blood.
In the T1DM milieu, CCR9⁺ Tregs become dysfunctional and shift towards a pro-inflammatory phenotype, thereby exacerbating the autoimmune response. The anti-IL-21 monoclonal antibody Avizakimab can reverse the dysfunction of CCR9⁺ Tregs and ameliorate disease symptoms by inhibiting the IL-21/IL-17 axis, providing a novel potential strategy for the immunotherapy of T1DM and highlighting the translational potential of targeting this axis.

PMID:
42694947
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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