Abstract
The anti-inflammatory cytokine IL-35 is produced by regulatory T (Treg) cells to suppress autoimmune and inflammatory responses. The role of IL-35 in type 1 diabetes (T1D) remains to be answered. To elucidate this, we investigated the kinetics of Treg cell response in the multiple low dose streptozotocin induced (MLDSTZ) T1D model and measured the levels of IL-35 in human T1D patients. We found that Treg cells were increased in MLDSTZ mice. However, the Treg cells showed a decreased production of anti-inflammatory (IL-10, IL-35, TGF-β) and increased pro-inflammatory (IFN-γ, IL-2, IL-17) cytokines, indicating a phenotypic shift of Treg cells under T1D condition. IL-35 administration effectively both prevented development of, and counteracted established MLDSTZ T1D, seemingly by induction of Eos expression and IL-35 production in Treg cells, thus reversing the phenotypic shift of the Treg cells. IL-35 administration reversed established hyperglycemia in NOD mouse model of T1D. Moreover, circulating IL-35 levels were decreased in human T1D patients compared to healthy controls. These findings suggest that insufficient IL-35 levels play a pivotal role in the development of T1D and that treatment with IL-35 should be investigated in treatment of T1D and other autoimmune diseases.
Highlights
Which have lost their suppressive function, have been reported in chronic infections, autoimmune diseases and upon allograft rejection[20,21,22,23,24]
We have found that both tTreg and pTreg cells are upregulated during the early development of experimental Type 1 diabetes (T1D), but this upregulation could not protect against hyperglycemia
We found that IL-35 administration prevented the development of T1D and even reversed established T1D in two different mouse models
Summary
Which have lost their suppressive function, have been reported in chronic infections, autoimmune diseases and upon allograft rejection[20,21,22,23,24]. Pan et al have shown that the Ikaros transcription family member Eos, together with Foxp[3], is essential for maintaining the suppressive function of Treg cells[26], but the role of Eos has not yet been studied in autoimmune and infectious diseases It is not yet clear whether tTreg and/or pTreg cells switch their phenotype under autoimmune and inflammatory conditions. The kinetics of the novel anti-inflammatory cytokine IL-35 in autoimmune diseases, e.g. T1D is still unclear These unresolved questions urged us to examine and clarify the role of Treg cells during the early development of T1D, using the murine multiple low dose streptozotocin (MLDSTZ) induced T1D model[27], the NOD mouse model, and analysis of human peripheral blood obtained from T1D patients and healthy control subjects
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