Role of OX40/OX40L signaling in the expansion of regulatory T cells in the NOD mouse model (BA13P.127)

Abstract

Abstract Type 1 diabetes (T1D) is a T-cell-mediated disease characterized by destruction of pancreatic beta cells. Unfortunately, most treatment options for T1D are non-specific, with many side effects. Regulatory cells T (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. The therapeutic potential of Tregs has not been fully understood because generating large numbers of Tregs has remained a challenge. Recently, we reported that bone marrow precursor cells differentiated with GM-CSF (BMDCs) are able to selectively expand Tregs ex-vivo. Further investigation revealed that this expansion is TCR-independent but requires OX40/OX40L interaction. Thus, here we wanted to study whether treatment with soluble OX40L can expand Tregs in-vivo and in the NOD mice. Surprisingly, treatment with OX40L caused rapid onset of T1D in 12 wk but not 6 wk old mice. Analysis of spleens and lymph nodes showed an increase in Tregs only in the 6 wk old OX40L group. Thymic analysis revealed an increase in Tregs in both the 6 and 12 wk old OX40L groups. Interestingly, OX40L specifically induced the stable Tregs subset in 6 wk old mice, but the labile Treg subset in the 12 wk old mice. Based on these findings, we propose that OX40L can specifically induce different subsets of Tregs based on the cytokine milieu.