Induction of autoimmune diabetes in non‐obese diabetic mice requires interleukin‐21‐dependent activation of autoreactive CD8+ T cells. (4th July 2013)

• Record Type: Journal Article
• Authors: Chen, X.‐L.; Bobbala, D.; Rodriguez, G. M.; Mayhue, M.; Chen, Y.‐G.; Ilangumaran, S.; Ramanathan, S.
• Is Part Of: Clinical and experimental immunology. Volume 173:Number 2(2013:Aug.)
• Page Start: 184
• Page End: 194
• Publication Date: 2013-07-04
• Subjects: Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.12108
• Languages: English
• ISSNs: 0009-9104

Abstract

<abstract abstract-type="main"> <title>Summary</title> <p>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<sup>+</sup> T cells by increasing their antigen responsiveness. To investigate the role of IL‐21 in activating diabetogenic CD8<sup>+</sup> 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<sup>+</sup> T cells from the 8.3‐NOD.<italic>Il21</italic><sup>−<italic>/</italic>−</sup> 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 <italic>in vivo</italic> even in IL‐21‐sufficient mice. These cells also showed impaired IL‐2 production and <italic>Il2</italic> 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<sup>+</sup> 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<sup>+</sup> T cells, but may have to be combined with other strategies to inhibit already activated cells.</p> </abstract>