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 4

Anti-CD122 treatment alters immune compartment in pancreatic islets.

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Anti-CD122 treatment alters immune compartment in pancreatic islets. (A)...
(A) Representative FACS plots of immune cell profiles in pancreatic islets of NOD mice treated with control mAb or ChMBC7 for 7 weeks (from 3–10 weeks of age). (B) Statistical data of the percentages and numbers of indicated subsets from pancreatic islets of the mice treated in A (n = 7 in each group). (C) Representative FACS plots (upper) and statistics (lower) of CD8 subsets from mice as in A (n = 7). (D) Eight-week-old NOD/BDC2.5 mice were treated with control mAb or ChMBC7 for 2 weeks. Representative FACS plots (left) and statistics (right) of CD44+CD122hi subset within pancreatic CD8+ T cells (n = 3 in each group). (E) Representative FACS plots (left) and statistics (right) of Tregs from pancreatic islets of mice as in A. (F) The ratios between Tregs and pathogenic cells as indicated from mice as in A. Statistical data are mean ± SEM. Data are representative of 3 independent experiments. P values are calculated using Student’s t test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.