IL-27 induces the differentiation of Tr1-like cells from human naive CD4+ T cells via the phosphorylation of STAT1 and STAT3

IL-27, a member of IL-6/IL-12 cytokine family, is mainly produced by activated antigen presenting cells (APC). It has been demonstrated that IL-27 has the pro- and anti-inflammatory properties during immune responses. However, the signaling pathways that contribute to the cytokine generation are still unclear in humans. In the present study, we showed that IL-27 induced IL-10 and IFN-γ, but had no effect on IL-2, TNF-α and IL-4 production from human umbilical cord blood mononuclear cells (CBMCs). For purified naive CD4+ T cells, IL-27 elicited the differentiation of Tr1-like cells with expression of IL-10 and IFN-γ. Importantly, this induction was dependent on the signal transducer and activator of transcription (STAT) 1 and 3 factors. In addition, all of the phosphorylated STAT3 positive cells were also positive for phosphorylated STAT1, both of which could be inhibited by a JAK2/STAT inhibitor, AG490. However, there was no phosphorylation of STAT4, STAT5 and STAT6 in IL-27-stimulating conditions. Moreover, the biological function of IL-10 that was induced by IL-27 mainly enhanced the expression of CD16 without influencing CD14 expression on human monocytes. These data identify the function of IL-27 on the differentiation of human naive CD4+ T cells and demonstrate that the STATs signaling pathways may play an important role in mediating immune responses in humans.