title: Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse.
abstract: OBJECTIVE
  T helper type (Th) 17 cells have been shown to play important roles in mouse models of several autoimmune diseases that have been classified as Th1 diseases. In the NOD mouse, the relevance of Th1 and Th17 is controversial, because single-cytokine-deficient NOD mice develop diabetes similarly to wild-type NOD mice.
  
  
  METHODS
  We studied the impact of IL-17/IFN-γ receptor double deficiency in NOD mice on the development of insulitis/diabetes compared with IL-17 single-deficient mice and wild-type mice by monitoring diabetes-related phenotypes. The lymphocyte phenotypes were determined by flow cytometric analysis.
  
  
  RESULTS
  IL-17 single-deficient NOD mice showed delayed onset of diabetes and reduced severity of insulitis, but the cumulative incidence of longstanding diabetes in the IL-17-deficient mice was similar to that in wild-type mice. The IL-17/IFN-γ receptor double-deficient NOD mice showed an apparent decline in longstanding diabetes onset, but not in insulitis compared with that in the IL-17 single-deficient mice. We also found that double-deficient NOD mice had a severe lymphopenic phenotype and preferential increase in regulatory T cells among CD4(+) T cells compared with the IL-17 single-deficient mice and wild-type NOD mice. An adoptive transfer study with CD4(+)CD25(-) T cells from young non-diabetic IL-17 single-deficient NOD mice, but not those from older mice, showed significantly delayed disease onset in immune-deficient hosts compared with the corresponding wild-type mice.
  
  
  CONCLUSIONS
  These results indicate that IL-17/Th17 participates in the development of insulitis and that both IL-17 and IFN-γ signalling may synergistically contribute to the development of diabetes in NOD mice.
authors.affiliation: Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: G
authors.initials: G
authors.lastname: Kuriya
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.forename: S
authors.initials: S
authors.lastname: Akazawa
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: I
authors.initials: I
authors.lastname: Horie
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: H
authors.initials: H
authors.lastname: Yamasaki
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Nagayama
authors.forename: A
authors.initials: A
authors.lastname: Kawakami
authors.forename: N
authors.initials: N
authors.lastname: Abiru
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000172:deficiency* / Q000235:genetics; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008817:Mice, Mutant Strains; D016513:Mice, SCID
chemical_list: D001323:Autoantibodies; D020381:Interleukin-17; D007371:Interferon-gamma