“Alarming" T-Regulatory Cells (Tregs) to Protect from Type 1 Diabetes (T1D)

Defects in IL-2 signaling and Tregs correlate with susceptibility to T1D. Helminth burden also negatively correlates with the incidence of T1D. The alarmin IL-33 and its receptor ST2 are elicited in anti-helminth immunity, which also increase Tregs, M2 macrophages and Th2 response. We hypothesized that IL-33 may cooperate with IL-2 in promoting Tregs to protect from T1D. Indeed, a major subset of Tregs express ST2, thus enabling a role for IL-33 in Treg biology. Non-obese diabetic (NOD) mice, which have less Tregs than the nondiabetic NOD.Idd3 congenic mice, also exhibit less ST2⁺ Tregs (13±3%) than NOD.Idd3 (38±11%). For better cooperativity and preferential targeting of Tregs, we generated a hybrid cytokine (IL233) bearing IL-2 and IL-33 activities in a single molecule. Recent-hyperglycemia onset NOD mice (n≥6/group) were treated with daily injections (3.3pmol/g) of IL-2 and/or IL-33 or IL233 for 5 days. IL-33 alone offered a similar, if not better reversal of T1D with a 70% cumulative incidence (CI) compared to IL-2 alone (80% CI), whereas IL233 offered the best protection with 50% of mice remaining in remission 10-weeks post-treatment. There was a robust increase in the proportion of Tregs in pancreatic lymph node in IL233 group (25±3.7%) compared to 10±3.9%, 16±4.1%, 14±4.3% and 19±4.3% in Saline, IL-2 only, IL-33 only and IL-2 and IL-33 groups respectively. IL233 treatment also increased the levels of Tregs and group-2 innate lymphoid cells in an alternate species (rats) and blocked high-dose streptozotocin (STZ)-induced beta-cell death. Interestingly, the average islet size was bigger in the rats treated with IL233 in the STZ model, indicating a role of IL233 in islet growth and repair. Thus, IL233 utilizes the synergy of IL-2 and IL-33 to promote Tregs and bears strong therapeutic potential for T1D.