Broad induction of immunoregulatory mechanisms after a short course of anti-IL-7Rα antibodies in NOD mice

Abstract

Background: Type 1 diabetes is an autoimmune disease caused by T cell-mediated destruction of the insulin-producing β-cells in the pancreas. Therefore, approaches that effectively halt the pathogenic T cell response are predicted to have preventive or therapeutic benefit for type 1 diabetes patients. We previously demonstrated that long-term blocking of IL-7 signaling, which is critical for the survival and function of T cells, prevented and reversed type 1 diabetes in non-obese diabetic mice. However, such persistent inhibition of T cell responses raises concerns about causing immunodeficiency. Here, we asked whether a reduced duration of the treatment with anti-IL-7Rα antibodies retained efficacy in preventing diabetes. Moreover, we sought to identify immunoregulatory mechanisms induced by anti-IL-7Rα administration. Results: Anti-IL-7Rα antibodies were administered to prediabetic NOD mice for 3weeks and blood samples were taken at the end of treatment and 2weeks later to analyze changes in T cell phenotypes in response to IL-7Rα blockade. We found that the co-inhibitory receptors LAG-3, Tim-3 and PD-1 were increased on peripheral blood CD4+ and CD8+ T cells from anti-IL-7Rα-treated mice. Expression of these receptors contributed to reduced T cell cytokine production in response to TCR stimulation. In addition, the frequency of Tregs within the circulating CD4+ T cells was increased at the end of anti-IL-7Rα antibody treatment and these Tregs showed a more activated phenotype. In vitro restimulation assays revealed that effector T cells from anti-IL-7Rα-treated mice were more sensitive to co-inhibitory receptor induction after TCR stimulation. Importantly, these changes were accompanied by delayed type 1 diabetes disease kinetics. Conclusions: Together, our data show that short-term blockade of IL-7Rα induces detectable changes in co-inhibitory receptor expression and Treg frequencies in peripheral blood of NOD mice. These changes appear to have long-lasting effects by delaying or preventing type 1 diabetes incidence. Hence, our study provides further support for using anti-IL-7Rα antibodies to modulate autoreactive T cell responses.