Regulatory T cells and ST2 signaling control diabetes induction with multiple low doses of streptozotocin

Several peripheral mechanisms appear to be operational in limiting autoimmune damage of the islets of Langerhans and organ-specific T cell-mediated autoimmunity in general. These include cyclophosphamide sensitive T regulatory cells (Treg cells) and Th2 derived cytokine downregulation. We used the model of multiple low doses of streptozotocin (MLD-STZ) induced diabetes in susceptible C57BL/6 mice and resistant BALB/c mice to study these regulatory mechanisms. We show that low dose cyclophosphamide (CY) sensitive CD4⁺CD25⁺FoxP3⁺ Treg cell-dependent mechanisms can be demonstrated in C57Bl/6 mice susceptible to MLD-STZ diabetes induction. CY pretreatment decreased Foxp3⁺ cell count, glycemia, glycosuria and insulitis. In contrast, CY did not overcome resistance to diabetes induction in BALB/c mice. However, in BALB/c mice, deletion of ST2, an orphan member of the IL-1R family responsible for Th2 cell signaling leads to enhanced susceptibility to diabetes induction as evaluated by level of glycemia and glycosuria, number of infiltrating cells and β cell loss. RT-PCR analysis of mRNA transcripts of diabetogenic cytokines revealed that the expression of TNF-α, and IFN-γ was significantly enhanced in pancreatic lymph nodes by day 10 after diabetes induction in ST2-deficient mice in comparison with wild type BALB/c mice while IL-17 was detected only in ST2^-/- mice by day 21. Our results are compatible with the notion that Treg cells are involved in MLD-STZ diabetes in susceptible mice and demonstrate that ST2-mediated signaling may also be involved in limiting Th1/Th17-mediated autoimmune pathology in diabetes resistant strain.