IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses
Introduction
Both Th1 and Th17 responses have been connected to debilitating central nervous system diseases such as autoimmune uveitis and multiple sclerosis. Human autoimmune uveitis is a group of intraocular inflammatory diseases that affect the neural retina and are estimated to cause 10–15% of blindness in the western world [1]. Antigen specific CD4+ effector T cells have a central role in the pathogenesis and T cell directed therapies ameliorate disease. Published data on cytokine profiles of uveitis patients provide evidence that an elevated Th1 response is associated with some types of human uveitis [2], whereas a role for the Th17 response has been suggested in others [3], [4]. Similarly, both Th1 and Th17 responses are reported in patients with multiple sclerosis and different responses determine the efficacy of treatments [5].
Experimental autoimmune uveitis (EAU), induced by immunization with retinal antigen(s) that elicit memory responses in lymphocytes of uveitis patients, serves as a model for clinical autoimmune uveitis. As appears to be the case in the human disease, both Th1 and Th17 responses are generated and both are involved in pathogenesis of EAU. The data supporting this conclusion are: (i) EAU induced by active immunization with interphotoreceptor retinoid binding protein (IRBP) in CFA and EAU induced by infusion of IRBP-pulsed mature dendritic cells (DCs) were found to require, respectively, Th17 and Th1 responses; (ii) EAU could develop in mice deficient in IFN-γ or IL-17; (iii) polarized IL-17-producing Th17 or IFN-γ-producing Th1 uveitogenic T cells could induce full blown disease in recipients lacking the reciprocal signature cytokine [6], [7]. Similarly, experimental autoimmune encephalomyelitis (EAE) can also be induced by Th1 polarized and Th17 polarized cells independently [5]. Thus, either Th1 or Th17 effector response is capable of driving CNS autoimmune diseases.
Chronic autoimmune diseases, including uveitis and multiple sclerosis, are believed to involve continuous recruitment and priming of new effector T cells. It has become increasingly clear that immune responses have an inherent plasticity. Th1 and Th17 effectors derive from a common pool of Ag-specific precursors, which can be differentiated along either pathway. Therefore, therapeutic inhibition of one effector pathway might simply shunt the response to the other, equally pathogenic, lineage. This concept is supported by observations in animal models, showing that neutralization or deficiency of the Th1 signature cytokine IFN-γ leads to an elevated Th17 response, whereas deficiency of IL-17 leads to an elevated Th1 response [6], [8], [9]. The ideal therapy would thus be one that targets both the Th1 and the Th17 responses concurrently.
Type 1 cytokine receptors are transmembrane receptors with a conserved WSXWS motif that recognize and respond to cytokines with 4 α-helical strands such as IL-6, IL-12, IL-23 and IL-27, which are involved in T cell effector choices [10]. Among them, IL-6 signaling is required to mediate STAT3-dependent retinoic acid-related orphan receptor (RORγt) expression for Th17 polarization [11]. IL-27 signaling promotes Th1 polarization by inducing T box transcription factor (Tbet) expression through STAT1 and p38 MAPK phosphorylation [12], [13]. Both IL-6 and IL-27 receptors share a common β subunit, i.e. gp130, which is also shared with the receptors of other members in the IL-6 cytokine family [14]. Elimination of IL27Rα signaling inhibits the Th1 pathway, while blockade of IL-6R signaling inhibits the Th17 effector pathway, ameliorating EAU, similarly to direct targeting of IFN-γ or IL-17 [15], [16]. However, individual blockade of either the Th1 or the Th17 pathway, while effective in the short term, may be inadequate as a long-term treatment of chronic disease. Clinical evidence to support this notion derives, among others, from limited success of Th17-directed therapy in Behçet's uveitis [17] and Crohn's disease [18], although in both an association with Th17 had been reported, and from varying degrees of success with IFN-β therapy in different forms of multiple sclerosis [5].
IL-27p28, the α subunit of IL-27, is a natural antagonist of gp130, which is required for signaling by IL-27 and IL-6 receptors [19]. IL-27p28 was reported to control B cell responses and to inhibit differentiation of T cells towards the Th17 lineage by blocking gp130 [19]. However, very little is known about its other activities in controlling T cell-mediated autoimmune diseases. In the present study we use the EAU and EAE models of CNS autoimmunity to investigate the ability of IL-27p28 to concurrently regulate autopathogenic Th1 and Th17 responses in vivo, and we examine the associated mechanisms. We demonstrate that in vivo overexpression of IL-27p28 ameliorates actively induced EAU and EAE and reduces development of Th1 and Th17 responses, by interfering with Th1/Th17 lineage commitment through effects on STAT molecules and lineage-specific transcription factors. Importantly, IL-27p28 also ameliorated adoptively transferred EAU induced by already differentiated Th1 or Th17 cells and reduced effector cell numbers, at least in part by impeding lineage stability. Our findings suggest that IL-27p28 effectively suppresses acquisition as well as expression of Th1 and Th17 immunity, providing a potential approach to treatment of CNS and other autoimmune diseases where there is involvement of functionally redundant Th1/Th17 effector responses.
Section snippets
Mice
p28-TG mice in C57BL/6 background were generated by Zymogenetics, WA. These mice have no difference in the number of mature B cells and CD4+T/CD8+T cells ratio, but have relatively higher total numbers of CD4+ and CD8+ T cells in the spleen [19]. C57BL/6 and B10.RIII mice were purchased from The Jackson Laboratory (Bar Harbor, ME). IRBP161-180 T cell receptor transgenic mice (R161H) [60] were produced and bred in-house. All mice were kept in a specific pathogen-free facility and fed standard
IL-27p28 inhibits generation of Th1 and Th17 effector responses in vivo, and ameliorates EAU and EAE
To examine whether IL27-p28 affects susceptibility to EAU, we immunized IL-27p28 transgenic mice on the C57BL/6 background (p28-TG) [19] and their wild type (WT) littermates with the uveitogenic retinal antigen, IRBP. p28-TG mice developed significantly lower disease scores than their WT littermates and had fewer IL-17A and IFN-γ producing CD4+ T cells in their eyes (Fig. 1A and B). GM-CSF has recently been identified as the shared effector molecule of both Th1 and Th17 effector CD4+ T cells
Discussion
Data from our laboratory as well as from others support the notion that autoimmunity in the CNS and possibly also other tissues involves both Th1 and Th17 effector responses, with each lineage separately able to drive specific pathology. The inherent plasticity of effector responses therefore raises a concern that targeting either Th1 or Th17 cells may shift the balance of effector response towards the alternative pathway without reducing pathology, and could possibly explain the disappointing
Conclusion
In conclusion, we demonstrated that IL-27p28, a natural antagonist of gp130, modulated the autoimmunity in CNS by concurrently suppressing the commitment and the subsequent lineage stability of autoaggressive Th1 and Th17 cells. This effect is achieved at least in part by blocking the IL27-mediated STAT1 and IL6-mediated STAT3 phosphorylation, which leads to the inhibition of Tbet and RORγt expression in Th1 and Th17 cells. Finally, IL-27p28 suppressed both IL-27 mediated Th1 and IL-6 mediated
Acknowledgments
The authors thank the NEI the Flow Cytometry Core and Histology facilities. We thank Dr. Wei Lai for technical advice on human T cell polarization. We thank Olivia Schneider of Shenandoah Biotechnology for the IL-27p28 plasmid. We are grateful to Dr. Christopher Hunter (University of Pennsylvania) for supplying to us the ZymoGenetics p28 TG mice. The study was supported by NIH/NEI Intramural funding, project # EY000184-29.
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Authors share equal contribution.