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 6

Anti-CD122 treatment prevents the conversion of Th17 cells to pathogenic Th1 cells in the pancreas.

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Anti-CD122 treatment prevents the conversion of Th17 cells to pathogenic...
(A) The percentages of Th17 cells in pancreatic islets of 10-week-old NOD mice treated with control mAb or ChMBC7 for 7 weeks (n = 7 in each group). (B) Schematic diagram showing experimental design of Th17 transfer experiments. (C) Representative FACS plots of IL-17A and IFN-γ expression in donor cells before and after the transfer. (D and E) IFN-γ and IL-17A production by donor CD4+ T cells from pancreatic islets (D) and spleen (E) in recipient mice treated with either control mAb or ChMBC7 (n = 5 in each group). Data are representative of 3 (A) or 2 (B–E) independent experiments. Statistical data are mean ± SEM. P values are calculated using Student’s t test. *P < 0.05; **P < 0.01.