Non-obese diabetic (NOD) mice lacking IL-21 or IL-21 receptor do not develop autoimmune type 1 diabetes (T1D). We have recently shown 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 MHC class-I-restricted 8.3 transgenic TCR. IL-21 deficiency completely protected 8.3-NOD mice 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 ... More
Non-obese diabetic (NOD) mice lacking IL-21 or IL-21 receptor do not develop autoimmune type 1 diabetes (T1D). We have recently shown 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 MHC class-I-restricted 8.3 transgenic TCR. IL-21 deficiency completely protected 8.3-NOD mice 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 prior antigen stimulation enabled these cells to cause diabetes in NOD.scid recipients. The 8.3 T cells that developed in 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 completely reverse their impaired proliferation. 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 naïve autoreactive CD8+ T cells, but may have to be combined with other strategies to inhibit already activated cells.
