Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
Clin Exp Immunol. 2013 Aug;173(2):184-94. doi: 10.1111/cei.12108.
Non-obese diabetic (NOD) mice lacking interleukin (IL)-21 or IL-21 receptor do not develop autoimmune type 1 diabetes (T1D). We have shown recently that IL-21 may promote activation of autoreactive CD8(+) T cells by increasing their antigen responsiveness. To investigate the role of IL-21 in activating diabetogenic CD8(+) T cells in the NOD mouse, we generated IL-21-deficient NOD mice expressing the highly pathogenic major histocompatibility complex (MHC) class-I-restricted 8.3 transgenic T cell receptor (TCR). IL-21 deficiency protected 8.3-NOD mice completely from T1D. CD8(+) T cells from the 8.3-NOD.Il21(-/-) mice showed decreased antigen-induced proliferation but displayed robust antigen-specific cytolytic activity and production of effector cytokines. IL-21-deficient 8.3 T cells underwent efficient homeostatic proliferation, and previous antigen stimulation enabled these cells to cause diabetes in NOD.Scid recipients. The 8.3 T cells that developed in an IL-21-deficient environment showed impaired antigen-specific proliferation in vivo even in IL-21-sufficient mice. These cells also showed impaired IL-2 production and Il2 gene transcription following antigen stimulation. However, IL-2 addition failed to reverse their impaired proliferation completely. These findings indicate that IL-21 is required for efficient initial activation of autoreactive CD8(+) T cells but is dispensable for the activated cells to develop effector functions and cause disease. Hence, therapeutic targeting of IL-21 in T1D may inhibit activation of naive autoreactive CD8(+) T cells, but may have to be combined with other strategies to inhibit already activated cells.
非肥胖型糖尿病（NOD）小鼠缺乏白细胞介素（IL）-21 或 IL-21 受体不会发生自身免疫性 1 型糖尿病（T1D）。我们最近表明，IL-21 可能通过增加自身反应性 CD8+T 细胞的抗原反应性来促进其激活。为了研究 IL-21 在激活 NOD 小鼠中致糖尿病 CD8+T 细胞中的作用，我们生成了表达高致病性主要组织相容性复合物（MHC）I 类限制性 8.3 转基因 T 细胞受体（TCR）的 IL-21 缺陷型 NOD 小鼠。IL-21 缺陷完全保护 8.3-NOD 小鼠免受 T1D 的侵害。来自 8.3-NOD.Il21(-/-)小鼠的 CD8+T 细胞显示出抗原诱导的增殖减少，但表现出强大的抗原特异性细胞毒性活性和效应细胞因子的产生。IL-21 缺陷型 8.3 T 细胞经历了有效的同源性增殖，并且先前的抗原刺激使这些细胞能够在 NOD.Scid 受体中引起糖尿病。在缺乏 IL-21 的环境中发育的 8.3 T 细胞即使在 IL-21 充足的小鼠中也表现出抗原特异性增殖受损。这些细胞在抗原刺激后也表现出 IL-2 产生和 Il2 基因转录受损。然而，添加 IL-2 并不能完全逆转其增殖受损。这些发现表明，IL-21 是初始激活自身反应性 CD8+T 细胞所必需的，但对于激活的细胞发展效应功能和引起疾病是可有可无的。因此，T1D 中 IL-21 的治疗靶向可能会抑制幼稚自身反应性 CD8+T 细胞的激活，但可能需要与其他策略相结合以抑制已激活的细胞。
