IL-35-mediated induction of a potent regulatory T cell population

Abstract

Regulatory T cells (T reg cells) have a critical role in the maintenance of immunological self-tolerance. Here we show that treatment of naive human or mouse T cells with IL-35 induced a regulatory population, which we call 'iTR35 cells', that mediated suppression via IL-35 but not via the inhibitory cytokines IL-10 or transforming growth factor-β (TGF-β). We found that iTR35 cells did not express or require the transcription factor Foxp3, and were strongly suppressive and stable in vivo. T reg cells induced the generation of iTR35 cells in an IL-35- and IL-10-dependent manner in vitro and induced their generation in vivo under inflammatory conditions in intestines infected with Trichuris muris and within the tumor microenvironment (B16 melanoma and MC38 colorectal adenocarcinoma), where they contributed to the regulatory milieu. Thus, iTR35 cells constitute a key mediator of infectious tolerance and contribute to T reg cell–mediated tumor progression. Furthermore, iTR35 cells generated ex vivo might have therapeutic utility.