CD70 Inversely Regulates Tregs and iNKT Cells and Modulates Type 1 Diabetes in NOD Mice

The CD27-CD70 costimulatory pathway is essential for the full activation of T cells, but some studies show that blocking this pathway exacerbates certain autoimmune disorders. Herein, we report on the impact of CD70/CD27 signaling on disease progression in the NOD mouse model of type 1 diabetes (T1D). Specifically, our data demonstrates that CD70 ablation alters thymocyte selection and increases circulating T cell levels. CD27 signaling was particularly important for the thymic development and peripheral homeostasis of Foxp3 + Helios + regulatory T cells (Tregs), which likely accounts for our finding that CD70-deficient NOD mice develop more aggressive T1D onset. Interestingly, we found that CD27 signaling suppresses the thymic development and effector functions of T1D-protective invariant natural killer T (iNKT) cells. Thus, rather than providing costimulatory signals, the CD27-CD70 axis may represent a coinhibitory pathway for this immunoregulatory T cell population. Moreover, we showed that a CD27 agonist Ab reversed the effects of CD70 ablation, indicating that the phenotypes observed in CD70-deficient mice were likely due to a lack of CD27 signaling. Collectively, our results demonstrate that the CD27-CD70 costimulatory pathway regulates the differentiation program of multiple T cell subsets involved in T1D development, and may be subject to therapeutic targeting.