阻断 CD122 可通过多种机制恢复自身免疫 1 型糖尿病的免疫耐受。
CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms.
机构信息
Pediatric Diabetes Research Center, Department of Pediatrics, UCSD, La Jolla, California, USA.
JN Biosciences, Mountain View, California, USA.
出版信息
JCI Insight. 2018 Jan 25;3(2). doi: 10.1172/jci.insight.96600.
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.
摘要
IL-2/IL-15Rβ（CD122）信号对于 T 细胞和 NK 细胞的分化和功能至关重要。一种针对 CD122 的单克隆抗体已被证明可抑制动物模型中的自身免疫 1 型糖尿病（T1D）的发展。然而，其机制仍知之甚少。我们发现，体内给予抗 CD122 单克隆抗体（CD122 阻断）通过多种机制在非肥胖型糖尿病（NOD）小鼠中恢复免疫耐受。首先，CD122 阻断选择性地从胰岛中清除致病性 NK 细胞和记忆表型 CD8+T 细胞。相比之下，胰岛 CD4+Foxp3+Tregs 仅受到轻度影响。其次，CD122 阻断抑制胰岛免疫细胞中 IFN-γ 的产生。第三，CD122 阻断抑制胰岛 Th17 细胞向致糖尿病 Th1 细胞的转化。此外，抗 CD122 单克隆抗体和 Treg 营养细胞因子（IL-2 或 IL-33）的组合增强了胰岛 Tregs 的丰度和功能。总之，这些数据为 CD122 阻断介导的免疫调节提供了重要的机制见解，并支持这种联合治疗在 T1D 中的治疗益处。
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