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Clin Exp Immunol. 2013 Aug;173(2):184-94. doi: 10.1111/cei.12108.

Induction of autoimmune diabetes in non-obese diabetic mice requires interleukin-21-dependent activation of autoreactive CD8⁺ T cells.

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  • 1Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.

Abstract

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.

© 2013 British Society for Immunology.

KEYWORDS:

CD8+ T cells; IL-2; IL-21; NOD mouse; type 1 diabetes

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