IL-35Ig-expressing dendritic cells induce tolerance via Arginase 1

The cytokine interleukin IL-35 is known to exert strong immunosuppressive functions. Indoleamine 2,3-dioxygenase 1 (IDO1) and Arginase 1 (Arg1) are metabolic enzymes that, expressed by dendritic cells (DCs), contribute to immunoregulation. Here, we explored any possible link between IL-35 and the activity of those enzymes. We transfected a single chain IL-35Ig gene construct in murine splenic DCs (DC₃₅ ) and assessed any IDO1 and Arg1 activities as resulting from ectopic IL-35Ig expression, both in vitro and in vivo. Unlike Ido1, Arg1 expression was induced in vitro in DC₃₅ , and it conferred an immunosuppressive phenotype on those cells, as revealed by a delayed-type hypersensitivity assay. Moreover, the in vivo onset of a tolerogenic phenotype in DC₃₅ was associated with the detection of CD25⁺ CD39⁺ , rather than Foxp3⁺ , regulatory T cells. Therefore, Arg1, but not Ido1, expression in DC₃₅ appears to be an early event in IL-35Ig-mediated immunosuppression.