IL-27: Balancing T Cell-Mediated Immune Responses

Interleukin-27 (IL-27) is a member of the IL-12 family of heterodimeric cytokines that also includes IL-12, IL-23, and IL-35. Each of these cytokines consists of an alpha (p19, p28, or p35) and a beta (p40 or EBI3) chain and signals through receptors that are highly expressed on T cells and/or natural killer cells. IL-27 is comprised of p28, a polypeptide related to IL-12 p35, and EBI3 (Epstein-Barr virus-induced gene 3), an IL-12/IL-23 p40-related protein.1 It binds to a heterodimeric receptor complex formed by TCCR/WSX-1 and gp130, a common receptor subunit shared by IL-6 family cytokines.2 Upon secretion by activated antigen-presenting cells, IL-27 promotes the expansion of naïve CD4+ T cells, and drives Th1 differentiation by inducing the expression of the Th1-specific transcription factor, T-bet.2, 3, 4 At the same time, IL-27 in the absence of IL-4 inhibits the expression of the Th2-specific transcription factor, GATA-3, and suppresses Th2 cytokine production.3, 5 Despite its role in promoting Th1 differentiation, studies performed using TCCR/WSX-1-deficient mice infected with various pathogens suggest that IL-27 signaling is also required to prevent excessive T cell activity and limit pro-inflammatory cytokine production.6, 7 The importance of the anti-inflammatory properties of IL-27 was highlighted in 2006 when Batten et al. and Stumhofer et al. demonstrated that IL-27 could suppress the development of IL-17-producing Th17 cells.8, 9 Together these studies indicated that IL-27 may be important for inhibiting the pathogenesis of Th17-related inflammatory/autoimmune diseases.

IL-27 Has Both Pro- and Anti-Inflammatory Effects. IL-27 is a heterodimeric cytokine secreted by activated antigen-presenting cells.
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IL-27 Has Both Pro- and Anti-Inflammatory Effects. IL-27 is a heterodimeric cytokine secreted by activated antigen-presenting cells. It drives inflammation by promoting the early commitment of naïve CD4+ T cells to a Th1-specific lineage. In contrast, it inhibits inflammation by suppressing Th17 differentiation and inducing a T regulatory (Tr1)-like activity in differentiated Th1 and Th2 effector cells. IL-10 secretion by these cells has anti-inflammatory, immunosuppressive effects that may serve as a negative feedback mechanism to balance IL-27-induced Th1 differentiation. Recent evidence suggests that the p28 subunit of IL-27 may form a second protein complex with cytokine-like factor 1 (CLF), which is also involved in regulating the balance between pro- and anti-inflammatory T cell responses.

Recent reports have provided more details on the mechanisms by which IL-27 negatively regulates Th17 differentiation and inflammation. Using human or mouse naïve CD4+ T cells cultured under Th17-inducing conditions, IL-27 was shown to inhibit expression of the Th17-specific transcription factor, RORgamma t, and subsequent secretion of IL-17A.10 Consistent with published results, IL-27 also induced IL-10 production, suggesting a second mechanism by which it may regulate the pathogenicity of Th17 cells.10, 11, 12 To test the in vivo function of IL-27, mice lacking the p28 subunit of IL-27 were generated and immunized with myelin oligodendrocyte glycoprotein to induce experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.10 Similar to TCCR/WSX-1-deficient mice, IL-27 p28-deficient mice were more susceptible to EAE and developed a significantly more severe form of the disease. The increase in disease severity was associated with elevated expression of Th17-related molecules in the central nervous system, and reduced late phase expression of IL-10.

These results were confirmed in part by Murugaiyan et al., who also found that IL-27 could induce the production of IL-10 and IFN-gamma, and inhibit IL-17 secretion by anti-CD3, anti-CD28-activated human CD4+ T cells.13 This was accompanied by reduced expression of GATA-3 and RORC. Addition of IL-2 to activated T cells significantly enhanced IL-27-induced IL-10 secretion, while a neutralizing antibody to IL-2 inhibited IL-10 production. These characteristics were reminiscent of the phenotype of Tr1 cells, a subset of CD4+FoxP3+/– IL-10+ T regulatory (Treg) cells that expand in the presence of IL-2, suggesting that IL-27 may in part confer a Tr1-like activity on CD4+ T cells.14 Supporting this hypothesis, the supernatants from activated, IL-27-treated T cells suppressed the proliferation of freshly purified CD4+ T cells in an IL-10-dependent manner.13 Collectively, these studies highlight the pivotal role that IL-27 plays in regulating the delicate balance between pro-inflammatory Th1/Th17 cells and anti-inflammatory IL-10-producing T cell populations.

Crabe et al. have also recently described another secreted complex that consists of the p28 subunit of IL-27 and cytokine-like factor 1 (CLF).15 Like IL-27, p28/CLF is secreted by activated dendritic cells, but it requires TCCR/WSX-1, gp130, and IL-6 R alpha for signaling. In contrast to IL-27, p28/CLF not only inhibited the proliferation of mouse naïve CD4+ T cells, but it also induced the expression of IL-17 in the presence of TGF-beta. The level of IL-17 expression was comparable to that induced by TGF-beta and IL-6, when followed by PMA/ionomycin re-stimulation, demonstrating that p28/CLF could substitute for IL-6 in promoting mouse Th17 differentiation. IL-27 suppressed IL-17 expression in both circumstances, suggesting that it acts as an antagonist of both p28/CLF and IL-6 under these conditions. Further studies are necessary to determine the in vivo significance of p28/CLF, and whether this complex is relevant in humans. However, initial in vitro characterization indicates that it too may be involved in the regulation of inflammation and autoimmune diseases.


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