Divergent Effects of OX40L on Regulatory T Cell Phenotype and Function: Implications for Type 1 Diabetes Therapy

Type 1 diabetes mellitus (T1D) is a T-cell mediated disease characterized by destruction of pancreatic β-cells, resulting in life-long dependence on insulin therapy. Unfortunately, most treatment options for T1D are non-specific, not curative and have many side effects. Foxp3+ T regulatory cells (Tregs) play a crucial role in the maintenance of immune homeostasis against self-antigen. Many studies have revealed that Tregs in patients with various autoimmune diseases, including T1D, are diminished in number and/or dysfunctional. Unfortunately, the therapeutic potential of Tregs has not been fully understood as the risk of effector T cell contamination and the tendency of Tregs to lose their suppressive function upon repeated proliferation remain as central challenges. Recently, we demonstrated a critical role for OX40L/OX40 signaling in Treg expansion by bone marrow-derived dendritic cells (BMDCs). OX40L, expressed on APCs, binds to OX40 on T cells. Signaling through OX40 has been shown to play an important role in effector T cell proliferation and survival. However, its role in Treg biology is still controversial. Thus, in this study, we wanted to further determine the role of OX40L on Treg function and homeostasis in the non-obese diabetic (NOD) mouse, a well-established model for T1D. Our findings suggest that OX40L has divergent effects on Treg phenotype and disease onset depending on the age of the animal. Treatment of 12-week-old NOD mice resulted in rapid onset of hyperglycemia and an inability to expand Tregs in the periphery. In contrast, treatment of 6-week-old NOD mice induced significant expansion of Tregs. Further, our data suggest that OX40L expands Tregs in the thymus. Upon migration to the periphery, expanded Tregs undergo rapid conversion resulting in loss of Foxp3 expression in 12-week-old NOD mice. The inability to expand and sustain Treg survival in the periphery is most likely due to suboptimal IL-2 levels in 12-week-old NOD mice. Co-administration of OX40L/IL- 2 resulted in sustained Treg expansion in the periphery of 12-week-old mice. Thus, we propose that OX40L is required to drive Treg proliferation in the thymus, while IL-2 is required to sustain Treg survival in the periphery of NOD mice.