APC-derived cytokines and T cell polarization in autoimmune inflammation (original) (raw)

The evidence discussed above clearly argues against a role for IFN-γ–secreting Th1 cells in the pathogenesis of autoimmune disease and suggests a more regulatory role for this subset (_Evidence for Th17 pathogenesis in autoimmunity). However, given the known actions of IL-18, as well as the previously discussed role of T-bet, this paradigm cannot be completely dismissed. IL-18 is an 18-kDa proinflammatory cytokine and a member of the IL-1 superfamily of cytokines, although its activities are more similar to those of IL-12. It is, like IL-12, expressed by macrophages and DCs but also by epithelial cells, keratinocytes, and other stromal cells. It signals through the IL-18R, a heterodimeric complex of an IL-18Rα–binding subunit and an IL-18Rβ signaling subunit (also termed IL-1RAcPL or IL-1R7). The extracellular portion of IL-18Rα is responsible for IL-18 binding. However, this requires the presence of the receptor β subunit, which comprises the high-affinity receptor complex. IL-18R is expressed by a variety of immune cells, including lymphocytes, NK cells, macrophages, and neutrophils. As a result, IL-18 has pleiotrophic effects, although it is best known for its promotion of Th1 differentiation and IFN-γ production through its synergistic activities with IL-12 (Figure 2). It can also independently stimulate the cytotoxic activities of NK cells. It has previously been shown that IL-18–/– mice are protected from MOG35–55–induced EAE and are unable to mount autoreactive Th1 responses (71). The defective Th1 cell response was suggested to result at least in part from abrogated IFN-γ production by NK cells, as transfer of NK cells from RAG-deficient, but not from IFN-γ–/–, mice was able to rescue the susceptibility of these mice to EAE. In CIA, IL-18 deficiency reduced disease severity and incidence, characterized by decreased TNF-α in serum and spleen cultures and suppressed CII-specific Th1 responses (72). Administration of recombinant IL-18 to mice with CIA significantly enhances disease, with increased synovial hyperplasia, cellular infiltration, and cartilage erosion being observed (73). The effects of IL-18 are of a proinflammatory nature, as a significant increase in the production of IFN-β, TNF-α, and IL-6 occurred in these mice (74). The effects of IL-18 on bone and cartilage remain controversial, as both stimulatory and inhibitory effects on osteoclast formation have been reported (75–77). In contrast, a role for Th17 cells and Th17-mediated osteoclastogenesis in inducing autoimmune arthritis–related bone destruction has recently been established (78).

The discovery that IL-12 is superfluous during autoimmune pathogenesis while IL-18 is an absolute necessity raised the question of whether there is redundancy in the system whereby IL-18 can function in the absence of IL-12 to induce autoimmunity. We recently were able to show that this was not the case, as mice deficient in both IL-12p35 and IL-18 were still fully susceptible to MOG peptide–induced EAE (79). On further analysis, and in contrast to the previous report, we discovered that IL-18–deficient mice were fully susceptible to EAE. Furthermore, IL-18–/– mice produced T cell responses and IFN-γ levels that were identical to those of WT mice. Despite a clear contradiction between our findings and those of Shi et al. (71, 79), this was not the first time that a redundant role for IL-18 has been described in a model of autoimmune disease. Santos et al. used a model of autoimmune arthritis known an antigen-induced arthritis (AIA) that is induced with methylated BSA in CFA and, in contrast to CIA, is dependent on cell-mediated immunity only (80). Applying this model, they were able to show that IL-18 is not required for AIA, nor is it necessary as a Th1 response cofactor and inflammatory cytokine (80). The conflicting results described for IL-18 in EAE and AIA models have been postulated to result from several possible causes. Differences in backcrossing or the health status of the mouse are likely to be the main reasons, while, in the arthritis model, variability may have resulted from the divergent pathogenic mechanisms of these models. However, genetic background of the mice may also play a role. While IL-18–/– mice were backcrossed to the arthritis-susceptible DBA/1 background for CIA induction, AIA experiments were performed in IL-18–/– mice backcrossed onto the C56BL/6 background. Speaking against this hypothesis is the demonstration that IL-18–deficient mice on a DBA/1 background are not protected from ocular experimental autoimmune uveoretinitis (EAU), an autoimmune disease targeting photoreceptor antigens of the eye (81). It would nevertheless be of significant interest to determine the susceptibility of IL-18–/– mice to CIA that are not on the DBA background.

We felt that studying the susceptibility of IL-18Rα–/– mice to EAE could potentially shed light on the conflicting data discussed above. In contrast to the emerging nonpathogenic role for IL-18 in autoimmunity, which is in line with the changing Th1/Th2 paradigm, we discovered that IL-18Rα deletion induces resistance to EAE development (79). The administration of anti–IL-18Rα Abs to IL-18–/– mice abrogated disease development both before and after disease onset, leading us to conclude that an alternative ligand exists that is capable of binding to and signaling through IL-18Rα to induce autoimmunity. Finally, IL-18Rα–/– mice failed to generate and/or sustain encephalitogenic Th17 cells. In this context, we discovered that IL-18Rα engagement on accessory cells, and not lymphocytes, results in defective IL-12/23p40 production.

In light of the fact that the affinity of IL-18 to IL-18Rα is weak (82) and that there are still a number of orphan ligands in the IL-1 superfamily, we propose that an unknown alternative ligand binds to IL-18Rα and a so-far-unidentified signaling subunit expressed on APCs. Engagement of the IL-18Rα by this ligand supports the production of IL-23 necessary for the consequent expansion of Th17 cells.

Strengthening the findings that IL-18Rα is capable of interacting with a ligand other than IL-18, Lewis and Dinarello recently showed opposite responses in the rejection of IL-18–/– and IL-18Rα–/– pancreatic islets (83), which led the authors to propose the existence of an IL-18–independent inhibitory pathway that converges with the proinflammatory IL-18 signaling pathway at the IL-18R. Furthermore, they suggest the involvement of IL-1F7, a member of the IL-1 family that binds IL-18 binding protein (IL-18BP) and IL-18Rα, thereby inhibiting IL-18 activity.

Taken together, the data indicate that the polarization of Th17 cells clearly correlates with pathogenicity, while APC-derived cytokines have a critical role in polarizing T cells toward this autoimmunogenic phenotype (84). Thus, it would be of interest to reassess the role of the Th17-inducing cytokines IL-1, IL-6, and TGF-β in autoimmunity. It has long been known that both IL-1 and IL-6 are present in the synovial fluid of RA patients (85, 86), whereas in MS, IL-6 was upregulated in the plasma and CSF of MS patients, although no correlation between IL-6 levels and disease activity could be made (87). Correspondingly, IL-6–/– mice are protected from EAE and have delayed onset and reduced severity of CIA (88, 89). IL-1–/– mice are resistant to CIA, and IL-1R–/– mice are protected from EAE (90, 91). However, as IL-17 itself stimulates the production of both these molecules, this begs the question whether these in vitro Th17-inducing cytokines act upstream or downstream of IL-17. With regard to IL-1, Sutton et al. have provided evidence pointing to an upstream role for IL-1 (92). They showed that EAE resistance of IL-1R–/– mice results from deficient IL-17 production and that the adoptive transfer of encephalitogenic T cells can induce EAE in these mice (92). Furthermore, the spontaneous development of autoimmune arthritis in IL-1R antagonist–deficient (IL-1Ra–deficient) mice was completely prevented in mice on an IL-17–deficient background (93). Together, these data suggest that IL-1 is required for EAE during the development but not during the effector stages through its induction of Th17 cells. With regard to IL-6, Hirota et al. have demonstrated that the spontaneous occurrence of autoimmune arthritis in SKG mice results from Th17 cell development, but only in the presence of IL-6 (94). Therefore, IL-6 also appears to act upstream of Th17 cells. Adding complexity to the Th-17 pathway is the recent discovery that IL-25, also known as IL-17E and a member of the IL-17 family of cytokines, can regulate Th17 function in autoimmune inflammation (95). IL-25–/– mice are hypersusceptible to EAE as a result of increased IL-23 expression and a subsequent increase in the number of Th17 cells. The effects of IL-25 were mediated through elevation of IL-13, which in turn inhibits IL-23, IL-1β, and IL-6 expression in activated DCs (95).