Mast cells control insulitis and increase Treg cells to confer protection against STZ‐induced type 1 diabetes in mice

Abstract

Quantitative alterations in mast cell numbers in pancreatic lymph nodes (PLNs) have been reported to be associated with type 1 diabetes (T1D) progression, but their potential role during T1D remains unclear. In this study, we evaluated the role of mast cells in T1D induced by multiple low-dose streptozotocin (MLD-STZ) treatments, using two strains of mast cell-deficient mice (W/W v or Wsh/Wsh) and the adoptive transfer of mast cells.Mast cell deficient mice developed severe insulitis and accelerated hyperglycemia, with 100% of mice becoming diabetic compared to their littermates. In parallel, these diabetic mice had decreased numbers of T regulatory (Treg) cells in the PLNs. Additionally, mast cell deficiency caused a significant reduction in IL-10, TGF-β, and IL-6 expression in the pancreatic tissue. Interestingly, IL-6-deficient mice are more susceptible to T1D associated with reduced Treg-cell numbers in the PLNs, but mast cell transfer from wild-type mice induced protection to T1D in these mice. Finally, mast cell adoptive transfer prior to MLD-STZ administration conferred resistance to T1D, promoted increased Treg cells, and decreased IL-17-producing T cells in the PLNs. Taken together, our results indicate that mast cells are implicated in resistance to STZ-induced T1D via an immunological tolerance mechanism mediated by Treg cells.Keywords: Mast cell r Regulatory T cell r Tc17 cell r Th17 cell r Type 1 diabetes (T1D)Additional supporting information may be found in the online version of this article at the publisher's web-site Eur. J. Immunol. 2015Immunol. . 45: 2873Immunol. -2885 Introduction Type 1 diabetes (T1D) is an autoimmune disease that currently affects approximately 10-20 million people and is increasing in incidence worldwide. Similar to other autoimmune dysfunctions, the etiology of T1D is obscure. However, the development of the disease has been shown to be influenced by genetic and environmental factors including viral infections, food antigens, vaccinations, toxins, and stress [1,2]. T1D is characterized by pancreatic dysfunction resulting from the specific destruction of insulin-producing pancreatic β cells in the islets of Langerhans by autoreactive T lymphocytes. The onset of the hyperglycemia is preceded by a preclinical period designated as insulitis due to the infiltration of mononuclear cells, including T and B lymphocytes, monocytes, dendritic cells, and natural killer cells, into the pancreatic islets. Additionally, mast cell accumulation into the pancreatic islets has been reported prior to and at the onset of T1D in diabetic BB rats [3,4]. Regulatory T (Treg) cells are crucial for preventing the development of autoimmune diseases, maintaining self-tolerance and regulating the induction and intensity of the immune response to selfmolecules [5]. Previous studies have described the importance of Treg cells in the suppression of autoimmunity in an experimental T1D model, while specific IL-17-producing helper T cells (Th17) have been implicated in the promotion of the disease [6][7]...

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

“…26,65 In the STZ-induced diabetes model, Th2 immunity has been shown to be protective of insulitis development. 66 In concert with these results, levels of IL-17 were increased in pancreatic tissues of NOD mice already at 4-6 weeks of age, much before diabetes onset.…”

“…Inhibition of Th17 cells by anti–IL‐17 mAb neutralization, recombinant IL‐25 treatment, or use of Lactobacillaceae‐enriched probiotics prevent the development of T1D in NOD mice . In the STZ‐induced diabetes model, Th2 immunity has been shown to be protective of insulitis development . In concert with these results, levels of IL‐17 were increased in pancreatic tissues of NOD mice already at 4–6 weeks of age, much before diabetes onset.…”

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Zanthoxylum alkylamides ameliorate protein metabolism disorder in STZ-induced diabetic rats

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