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.
View Larger Image 		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.

References

  1. Pflanz, S. et al. (2002) Immunity 16:779.
  2. Pflanz, S. et al. (2004) J. Immunol. 172:2225.
  3. Lucas, S. et al. (2003) Proc. Natl. Acad. Sci. USA 100:15047.
  4. Takeda, A. et al. (2003) J. Immunol. 170:4886.Cites the use of R&D Systems Products
  5. Artis, D. et al. (2004) J. Immunol. 173:5626.
  6. Villarino, A. et al. (2003) Immunity 19:645.Cites the use of R&D Systems Products
  7. Hamano, S. et al. (2003) Immunity 19:657.
  8. Batten, M. et al. (2006) Nat. Immunol. 7:929.Cites the use of R&D Systems Products
  9. Stumhofer, J.S. et al. (2006) Nat. Immunol. 7:937.Cites the use of R&D Systems Products
  10. Diveu, C. et al. (2009) J. Immunol. 182:5748.Cites the use of R&D Systems Products
  11. Stumhofer, J.S. et al. (2007) Nat. Immunol. 8:1363.Cites the use of R&D Systems Products
  12. Fitzgerald, D.C. et al. (2007) Nat. Immunol. 8:1372.Cites the use of R&D Systems Products
  13. Murugaiyan, G. et al. (2009) J. Immunol. 183:2435.Cites the use of R&D Systems Products
  14. Roncarolo, M.G. et al. (2006) Immunol. Rev. 212:28.
  15. Crabe, S. et al. (2009) J. Immunol. 183:7692.Cites the use of R&D Systems Products

Cites the use of R&D Systems Products This symbol denotes references that cite the use of R&D Systems products.

Related Information

IL-12 Family
Th17 Cells