title: Induction of autoimmune diabetes in non-obese diabetic mice requires interleukin-21-dependent activation of autoreactive CD8⁺ T cells.
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.
authors.affiliation: Department of Pediatrics, Immunology Division, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: X-L
authors.initials: XL
authors.lastname: Chen
authors.forename: D
authors.initials: D
authors.lastname: Bobbala
authors.forename: G M
authors.initials: GM
authors.lastname: Rodriguez
authors.forename: M
authors.initials: M
authors.lastname: Mayhue
authors.forename: Y-G
authors.initials: YG
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Ilangumaran
authors.forename: S
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D000098546:Interleukin-21
chemical_list: D001324:Autoantigens; D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D000098546:Interleukin-21
keywords: CD8+ T cells; IL-2; IL-21; NOD mouse; type 1 diabetes