CD8+ regulatory T cells are critical in prevention of autoimmune-mediated diabetes

Chikako Shimokawa,Hajime Hisaeda,Hirokazu Arakawa,Takao Furuki,Noriyasu Ohshima,Seiji Obi,Tamotsu Kato,Kazutomo Suzue,Alex Olia,Tadashi Takeuchi,Takashi Izumi,Takashi Imai,Yoshiaki Ohtsu,Hiroshi Ohno,Minoru Sakurai

doi:10.1038/s41467-020-15857-x

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed. Intestinal helminths can cause asymptomatic chronic and immunosuppressive infections and suppress disease in rodent models of T1D. However, the underlying regulatory mechanisms for this protection are unclear. Here, we report that CD8+ regulatory T (Treg) cells prevent the onset of streptozotocin -induced diabetes by a rodent intestinal nematode. Trehalose derived from nematodes affects the intestinal microbiota and increases the abundance of Ruminococcus spp., resulting in the induction of CD8+ Treg cells. Furthermore, trehalose has therapeutic effects on both streptozotocin-induced diabetes and in the NOD mouse model of T1D. In addition, compared with healthy volunteers, patients with T1D have fewer CD8+ Treg cells, and the abundance of intestinal Ruminococcus positively correlates with the number of CD8+ Treg cells in humans.

Highlights

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed
Mice infected with an intestinal nematode, Heligmosomoides polygyrus (Hp), at 2 weeks before T1D induction showed mild elevation of blood sugar and maintained insulin concentrations consistent with conservation of β-cells (Fig. 1a–c)
These results demonstrate that infection with Hp protects mice from developing STZ-induced diabetes

Summary

Introduction

Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing pancreatic β-cells are destroyed. We report that CD8+ regulatory T (Treg) cells prevent the onset of streptozotocin -induced diabetes by a rodent intestinal nematode. Trehalose derived from nematodes affects the intestinal microbiota and increases the abundance of Ruminococcus spp., resulting in the induction of CD8+ Treg cells. IL-10 is reported to have important functions in IL-4deficient NOD mice[11] This nematode suppresses streptozotocin (STZ)-induced diabetes, and the protection is independent of IL-10 or Th2 polarisation through IL-4 signalling[12]. Molecular and cellular regulatory mechanisms underlying protection against T1D in intestinal helminthic infections are not clear As another environmental factor for increased prevalence of inflammatory disorders, recent studies indicate that the intestinal microbiota is associated with onset of some diseases. Compared with healthy volunteers, patients with T1D have fewer CD8+ Treg cells and intestinal Ruminococcus

Methods

Results

Conclusion