New directions in the basic and translational biology of interleukin-27

Abstract

Interleukin (IL)-27 is a member of the IL-6 and IL-12 family composed of the IL-27p28 and Epstein-Barr virus-induced gene 3 (EBI3) subunits. Although IL-27 was originally identified as a proinflammatory factor, subsequent studies have revealed the pleiotropic nature of this cytokine. This review discusses recent work that has explored the effect of IL-27 on CD4(+) T cell subsets, including T regulatory type 1 (Tr-1) cells, T follicular helper cells (Tfhs), and forkhead box P3 (Foxp3)(+) T regulatory cells (Tregs). Additionally, we highlight studies that have identified a role for the IL-27p28 subunit as a cytokine receptor antagonist. Much of the recent work on IL-27 has been relevant to human disease states characterized by inappropriate or excessive inflammation, and this review discusses potential opportunities to use IL-27 as a therapeutic agent.

Figure 1. IL-27 promotes the differentiation of Tr-1 cells and Tfh and inhibits Treg generation

IL-27 signaling on naïve CD4⁺ T cells can promote the differentiation of IL-10-producing Tr-1 cells by inducing expression of the transcription factor c-Maf in a STAT3-dependent manner. c-Maf transactivates the Il10 promoter to induce IL-10 production and promotes IL-21 production that supports the maintenance of Tr-1 cells. IL-27-induced AhR cooperates with c-Maf to optimize IL-10 and IL-21 expression. IL-27 signaling also can induce the generation of Tfh by increasing c-Maf expression and IL-21 production that promotes the survival and function of TFH as they interact with B cells. Finally, IL-27 signaling, in a partially STAT3-dependent manner, can also inhibit the generation of Foxp3-expressing Treg, although whether IL-27 acts directly or indirectly on differentiating Treg remains unclear.