Interleukin-35-mediated induction of a novel regulatory T cell population (49.7)

Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self tolerance and immune homeostasis. Due to their potent immunosuppressive properties, the ex vivo generation of regulatory T cells is an important goal of immunotherapy. We show that treatment of conventional T cells (Tconv) with the inhibitory cytokine IL-35 induces IL-35 expression and confers suppressive capacity, in the absence of Foxp3, IL-10 and TGFβ expression, upon Tconv cells. IL-35-dependent induced Tregs, termed iTR35, are strongly suppressive in vitro and in in vivo models including IBD, EAE, and a B16 tumor model. Treg-mediated suppression induces the generation of iTR35 in an IL-35- and IL-10-dependent manner in vitro and within the tumor microenvironment. Human IL-35 can mediate the generation of human iTR35 that express IL-35 and are suppressive. iTR35 may constitute a key mediator of infectious tolerance and ex vivo generated iTR35 may possess therapeutic utility in various human diseases.