Interleukin-27: balancing protective and pathological immunity

Abstract

It has been more than 15 years since the identification of individual interleukin-27 (IL-27) and IL-27 receptor components. The last decade has seen the description of the signaling pathways engaged by IL-27, and an appreciation has emerged that this cytokine can modulate the intensity and duration of many classes of T cell responses. Here we provide an overview of the immunobiology of IL-27 and review advances in understanding the functions of individual IL-27 and IL-27 receptor subunits and the role of IL-27 in dictating the balance between protective and pathological immunity. Additionally, this cytokine has been proposed as a therapy to modify inflammatory conditions or to promote antitumor responses, and situations where experimental and clinical data sets implicate IL-27 in the outcome of disease are highlighted.

Figure 1

Impact of IL-27 on lymphocyte signaling pathways. Dimerization of gp130 and IL-27Ra engages JAK1, 2 and Tyk2 that engage the MAPK pathway and activation of multiple STATs, most notably STAT1 and STAT3. The activation of STAT1 is linked to inhibition of GATA-3 and RoRγt but upregulation of PD-L1, T-bet and IL-10. The ability to engage STAT3 is linked to increased proliferation as well as IL-10 while the MAPK pathway intersects with AHR to promote IL-10 and IL-21.

Figure 2

Key regulatory effects of IL-27 on T and B cells. The pro-inflammatory properties attributed to IL-27 include the development of CTL, the promotion of TFH as well as a direct ability to promote B cell production of antibodies. The regulatory activities of IL-27 includes the ability to promote expression of the inhibitory receptor PD-L1 and IL-10 production by multiple helper T cells. The ability to generate a CXCR3+ Treg population is specialized to operate at sites of TH1 inflammation while the ability to control Th2 and Th17 inflammation is due to direct inhibitory effects on GATA3 and RoRgt.