Double deficiency in IL-17 and IFN-γ signalling significantly suppresses the development of diabetes in the NOD mouse

Abstract

Aims/hypothesis 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-cytokinedeficient NOD mice develop diabetes similarly to wildtype 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 wildtype 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/interpretation 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.

Interleukin-12: Functional activities and implications for disease

“…Today, this leads to the notion that both IL-12 and IL-23 as well as T H 1 and T H 17 cells are synergistically implicated in experimental autoimmune diabetes [61]. This matches with the finding that genetic ablation of the both effector cytokines IFN-γ and IL-17 acts synergistically to prevent diabetes [71].…”

Restoration of t cell substes of patients with type 1 diabetes mellitus by microencapsulated human umbilical cord Wharton jelly-derived mesenchymal stem cells: An in vitro study

“…It has been reported that IL-17 knock-out (KO) NOD mice showed a delayed onset of diabetes and milder insulitis, while the long-term follow-up of these animals revealed an incidence of the disease overlapping that of wild type animals [41]. These findings may suggest that IL-17 and therefore Th17 cells may be crucial for triggering autoimmunity in the early stages of the disease.…”

CD122 blockade restores immunological tolerance in autoimmune type 1 diabetes via multiple mechanisms

“…We thus propose a derepression model whereby ChMBC7 promotes Th17 cell differentiation by inhibiting the suppressive effect of IL-2. A number of studies have proposed that Th17 cells played a disease-promoting role in T1D (47,48), mainly through their signature cytokine IL-17 (49)(50)(51)(52)(53)(54) or, alternatively, through TNF-α produced by Th17 cells (55). However, this opinion was contradicted by other studies suggesting that Th17 cells may possess a disease-suppressive role in T1D (56)(57)(58)(59).…”