IL-23 Is Critical in the Induction but Not in the Effector Phase of Experimental Autoimmune Encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE), a T cell-mediated inflammatory disease of the CNS, is a rodent model of human multiple sclerosis. IL-23 is one of the critical cytokines in EAE development and is currently believed to be involved in the maintenance of encephalitogenic responses during the tissue damage effector phase of the disease. In this study, we show that encephalitogenic T cells from myelin oligodendrocyte glycopeptide (MOG)-immunized wild-type (WT) mice caused indistinguishable disease when adoptively transferred to WT or IL-23-deficient (p19 knockout (KO)) recipient mice, demonstrating that once encephalitogenic cells have been generated, EAE can develop in the complete absence of IL-23. Furthermore, IL-12/23 double-deficient (p35/p19 double KO) recipient mice developed EAE that was indistinguishable from WT recipients, indicating that IL-12 did not compensate for IL-23 deficiency during the effector phase of EAE. In contrast, MOG-specific T cells from p19KO mice induced EAE with delayed onset and much lower severity when transferred to WT recipient mice as compared with the EAE that was induced by cells from WT controls. MOG-specific T cells from p19KO mice were highly deficient in the production of IFN-γ, IL-17A, and TNF, indicating that IL-23 plays a critical role in development of encephalitogenic T cells and facilitates the development of T cells toward both Th1 and Th17 pathways.

Induction, function and regulation of IL‐17‐producing T cells

“…Treatment with anti-IL-23 reduced IL-17 production and attenuated EAU when administered immediately before and after induction of disease, but not at the effector stage of the disease, suggesting that IL-23 promotes the induction of murine Th17 cells in vivo [61]. This conclusion is consistent with a study in the EAE model involving adoptive transfer of T cells into IL-23p19 À/À mice, which concluded that IL-23 played a critical role in the development, but not effector function, of encephalitogenic T cells [62]. These studies, together with findings from my own group, showing that IL-23 can function with IL-1 to promote 'innate' IL-17 production from unconventional T cells in the absence of TCR engagement [25] (and Sutton and Mills, unpublished observations), suggest that the function of IL-23 is not to be confined to expansion of memory T cells.…”

“…While the differences observed using different experimental approaches and between human and mouse have not been fully resolved, the picture that is emerging is that multiple cytokines, including IL-1, IL-6, IL-21, TNF-a, IL-23 and TGF-b, stimulated by inflammatory stimuli, including TLR and NLR agonists and during sterile inflammation, can promote the differentiation or expansion of IL-17-secreting T cells. Studies with knockout mice have identified essential roles for IL-1 [25], IL-6 [59], IL-23 [62] and TGF-b [42] in the development of pathogenic T cells that mediated autoimmunity. These cytokines are obvious targets for the development of immunotherapeutics for autoimmune diseases.…”

“…This is consistent with a recent study on colitis, which demonstrated that IL-17-producing T cells are not required for the development of intestinal inflammation, but that IL-23 does have a pathogenic role by inhibiting Treg cells [85], and thereby enhancing Th1 responses. It has also been demonstrated that IL-23, as well as promoting IL-17 producing T cells, can enhance IFN-g-producing Th1 cells [62]. Thus, despite the initial assumptions that Th17, but not Th1, cells were the critical T cells that mediate the pathology in many autoimmune diseases, it now appears that Th1 cells may have both pathogenic and regulatory roles in certain autoimmune diseases, possibly at the induction and effector stages of disease.…”

CCR 7 Ligands Are Required for Development of Experimental Autoimmune Encephalomyelitis through Generating IL-23-Dependent Th17 Cells

“…5A). These results suggested that exogenous IL-23 was able to stimulate plt/plt mouse DLN cells along with the MOG peptide to induce pathogenic Th17 cells, consistently, with the critical role of IL-23 in the induction phase of EAE (17). Taken all together, these findings suggest that the defect in plt/plt mice is likely a defect in Th17 cell generation due to deficient IL-23 production.…”

“…4, A and D), indicating that the generation of IL-23 in response to CCR7 ligands is required for Th17 cell generation. Supporting this interpretation, recent reports have demonstrated that IL-23 is critically important in inducing Th17 cells (17,39,40). Taken together, it is possible that CCR7 ligands might also increase IL-21 production and IL-23 receptor expression for the optimal induction of Th17 cells.…”