IL-27 Priming of T Cells Controls IL-17-production in Trans Via Induction of PD-L1 (59.1)

Abstract Interleukin (IL)-27 is a key immunosuppressive cytokine that counters Th17-mediated pathology. To identify mechanisms by which IL-27 might exert its immunosuppressive effect, we analyzed genes in naïve CD4+ T cells rapidly induced by IL-27 stimulation for 3 hours. We discovered that IL-27 priming of naïve T cells upregulated expression of the ligand of PD-1 (PD-L1) in a STAT1-dependent manner. To assess the relevance of IL-27 in controlling PD-L1 expression in vivo, we employed a T. gondii infection model in which IL-27 is important for controlling immunopathology. We found that expression of PD-L1 on CD4+ T cells was significantly lower in EBI3-/- mice. When added to naïve CD4+ T cells, IL-27-primed T cells inhibited the differentiation of Th17 cells in trans in vitro. In vivo, co-administration of IL-27-primed T cells expressing PD-L1 inhibited the development of Th17 cells and protected from severe autoimmune encephalomyelitis. Moreover this inhibitory effect of IL-27 in vivo was largely reversed by elimination of PD-L1 on T cells. Thus, these data identify a novel suppressive activity of IL-27, by which CD4+ T cells can restrict differentiation of Th17 cells in trans. It is conceivable that the strategy of IL-27-pretreatment of naïve T cells ex vivo with subsequent adoptive transfer might be used therapeutically to attenuate autoimmune disease.