Faculty Collaboration Database

Induction of autoimmune diabetes in non-obese diabetic mice requires interleukin-21-dependent activation of autoreactive CD8a?? T cells. Clin Exp Immunol 2013 Aug;173(2):184-94

Date

04/24/2013

Pubmed ID

23607664

Pubmed Central ID

PMC3722919

DOI

10.1111/cei.12108

Scopus ID

2-s2.0-84880021592   11 Citations

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.

Author List

Chen XL, Bobbala D, Rodriguez GM, Mayhue M, Chen YG, Ilangumaran S, Ramanathan S

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Autoantigens
CD8-Positive T-Lymphocytes
Cell Proliferation
Cells, Cultured
Cytotoxicity, Immunologic
Diabetes Mellitus, Type 1
Interleukins
Lymphocyte Activation
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, Transgenic
Molecular Targeted Therapy
Receptors, Antigen, T-Cell