Cutting Edge: Human Regulatory T Cells Require IL-35 To Mediate Suppression and Infectious Tolerance

Human regulatory T cells (Treg) are essential for the maintenance of immune tolerance. However, the mechanisms they use to mediate suppression remain controversial. Although IL-35 has been shown to play an important role in Treg-mediated suppression in mice, recent studies have questioned its relevance in human Treg. In this study, we show that human Treg express and require IL-35 for maximal suppressive capacity. Substantial upregulation of EBI3 and IL12A, but not IL10 and TGFB, was observed in activated human Treg compared with conventional T cells (Tconv). Contact-independent Treg-mediated suppression was IL-35 dependent and did not require IL-10 or TGF-β. Lastly, human Treg-mediated suppression led to the conversion of the suppressed Tconv into iTr35 cells, an IL-35–induced Treg population, in an IL-35–dependent manner. Thus, IL-35 contributes to human Treg-mediated suppression, and its conversion of suppressed target Tconv into IL-35–induced Treg may contribute to infectious tolerance.