Antigen-specific prevention of type 1 diabetes in NOD mice is ameliorated by OX40 agonist treatment

Antigen-specific therapies are possibly the safest approach to prevent type 1 diabetes (T1D). However their clinical translation has yielded poor results and greater efforts need to be put into the development of novel strategies to ameliorate their clinical outcome. OX40 is a costimulatory molecule expressed by T cells after antigen recognition and has been implicated in the control effector but also regulatory T cells (Tregs) function in vivo. The activity of OX40 signal on Tregs function has been controversial. In this context we investigated whether an anti-OX40 agonist antibody treatment can ameliorate antigen-specific immune intervention for the prevention of T1D. We show that treatment of non-obese diabetic (NOD) mice with an OX40 agonistic antibody (OX86) reduced type 1 diabetes (T1D) incidence by inducing both CD4+CD25+Foxp3+ Tregs and CD4+Foxp3− T cells expressing the latency-associated peptide (LAP). These OX86-induced CD4+Foxp3−LAP+ T cells also demonstrated suppressive activity in vitro. A significant increase in protection was observed when OX86 was combined with insulin B9:23 (insB9:23) peptide immunizations. Synergy resulted from an expansion of IL-10-expressing insB9:23-reactive Tregs which augmented the proportion of CD4+ T cells with in vivo suppressive activity. Consequently, CD4+ T cells purified from OX86/insB9:23 combination treatment prevented T1D development when adoptively transferred into recipient mice. These findings suggest that the requirement for OX40 signaling by antigen-induced Tregs can be dominant over its well-documented need for effector memory cell function and may have potentially important implications for improving the clinical translation of antigen-specific prevention of T1D and possibly other autoimmune disorders.

► OX40 agonist antibody treatment of prediabetic NOD mice reduces diabetes incidence. ► Antigen-specific prevention of diabetes is ameliorated by OX40 agonist treatment. ► OX40 agonist antibody expands both CD4+CD25+Foxp3+ and CD4+LAP+ regulatory T cells.