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

Nemanja Zdravkovic, Allen Shahin, Nebojsa Arsenijevic, Miodrag L. Lukic, Eric P.K. Mensah-Brown

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)28-36
Number of pages9
JournalMolecular Immunology
Issue number1
Publication statusPublished - Nov 2009


  • Autoimmunity
  • CD25
  • Foxp3
  • IFN-γ
  • IL-17

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology


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