CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms
Xiaomei Yuan, Yi Dong, Naoya Tsurushita, J. Yun Tso, Wenxian Fu
Xiaomei Yuan, Yi Dong, Naoya Tsurushita, J. Yun Tso, Wenxian Fu
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Research Article Inflammation

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

Abstract

Signaling through IL-2/IL-15Rβ (CD122) is essential for the differentiation and function of T cells and NK cells. A mAb against CD122 has been implicated to suppress autoimmune type 1 diabetes (T1D) development in animal models. However, the mechanisms remain poorly understood. We find that in vivo administration of an anti-CD122 mAb (CD122 blockade) restores immune tolerance in nonobese diabetic (NOD) mice via multiple mechanisms. First, CD122 blockade selectively ablates pathogenic NK cells and memory phenotype CD8+ T cells from pancreatic islets. In contrast, islet CD4+Foxp3+ Tregs are only mildly affected. Second, CD122 blockade suppresses IFN-γ production in islet immune cells. Third, CD122 blockade inhibits the conversion of islet Th17 cells into diabetogenic Th1 cells. Furthermore, a combination of anti-CD122 mAb and Treg-trophic cytokines (IL-2 or IL-33) enhances the abundance and function of islet Tregs. In summary, these data provide crucial mechanistic insights into CD122 blockade–mediated immunoregulation and support therapeutic benefits of this combinational treatment in T1D.

Authors

Xiaomei Yuan, Yi Dong, Naoya Tsurushita, J. Yun Tso, Wenxian Fu

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Figure 1

Anti-CD122 treatment suppresses insulitis and diabetes in NOD mice.

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Anti-CD122 treatment suppresses insulitis and diabetes in NOD mice. (A) ...
(A) The percentages of NK cells from peripheral blood of 10-week-old NOD mice injected with 1 dose TM-β1 (5 mg/kg) or ChMBC7 (5 mg/kg) (n = 3) and analyzed at various time points as indicated. (B) The incidence of diabetes onset in female NOD mice treated with anti-CD122 (ChMBC7) (n = 14) or control mAb (n = 23) for 7 weeks (from 3–10 weeks of age). (C) Histology of formalin-fixed and H&E-stained pancreas sections from mice treated as in B (n = 3 in each group). Scale bar: 50 μm. (D) The numbers of CD45+ immune cells from each individual pancreas of control (n = 12) or ChMBC7-treated (n = 11) mice. Data are shown as mean ± SEM. Statistical data were calculated using Gehan-Breslow-Wilcoxon test (B) or Student’s t test (D). *P < 0.05.