Role of IL-12 Receptor β1 in Regulation of T Cell Response by APC in Experimental Autoimmune Encephalomyelitis

Abstract

IL-12 was thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disorder of the CNS. However, we have recently found that IL-12 responsiveness, via IL-12Rβ2, is not required in the induction of EAE. To determine the role of IL-12Rβ1, a key subunit for the responsiveness to both IL-12 and IL-23, in the development of autoimmune diseases, we studied EAE in mice deficient in this subunit of IL-12R. IL-12Rβ1−/− mice are completely resistant to myelin oligodendrocyte glycoprotein (MOG)-induced EAE, with an autoantigen-specific Th2 response. To study the mechanism underlying this Th2 bias, we cocultured purified CD4+ T cells and APCs of MOG-immunized mice. We demonstrate that IL-12Rβ1−/− APCs drive CD4+ T cells of both wild-type and IL-12Rβ1−/− mice to an Ag-induced Th2 phenotype, whereas wild-type APCs drive these CD4+ T cells toward a Th1 type. IL-12Rβ1−/− CD4+ T cells, in turn, appear to exert an immunoregulatory effect on the capacity of wild-type APCs to produce IFN-γ and TNF-α. Furthermore, decreased levels of IL-12p40, p35, and IL-23p19 mRNA expression were found in IL-12Rβ1−/− APCs, indicating an autocrine pathway of IL-12/IL-23 via IL-12Rβ1. IL-18 production and IL-18Rα expression are also significantly decreased in IL-12Rβ1−/− mice immunized with MOG. We conclude that in the absence of IL-12Rβ1, APCs play a prominent regulatory role in the induction of autoantigen-specific Th2 cells.

Divergent effects of IL‐12 and IL‐23 on the production of IL‐17 by human T cells

“…However, they provided no explanation for why abolishing IL-12(R)-mediated signaling in p35-or IL-12Rb2-deficient mice yielded a phenotype of enhanced disease susceptibility/severity [9][10][11][12]14]. Our finding of the exclusive capacity of IL-12 to suppress the release of IL-17 from activated human T cells provides a possible molecular mechanism behind this apparent anti-inflammatory activity of IL-12.…”

“…Accordingly, Zhang et al [13] reported that IL-12Rb1-deficient mice are resistant to EAE. Unexpectedly, however, IL-12p35-and IL-12Rb2-deficient mice, in which only the IL-12 and not the IL-23 function is affected, are more susceptible and developed more severe pathology than wild-type mice [9,10,12,13], with increased levels of IL-23p19 in spleen cells compared to wild-type littermates [13,14]. It was concluded from these studies that IL-12 is not critical for disease development, and may even play an undefined protective role.…”

Antigen presenting cells treated in vitro by macrophage colony-stimulating factor and autoantigen protect mice from autoimmunity

“…In mice, APCs that produce large quantities of IL-12 and IFN-γ induce Th1 responses; APCs that produce low amounts of IL-12 but a high level of MCP-1 preferentially induce Th2 responses, whereas APCs that produce a low level of IL-12 but a high level of IL-10 induce regulatory T cell (Tr) responses (de Jong et al, 2005). In addition, our laboratory found that APCs of IL-12Rβ1 −/− mice, which lack both IL-12 and IL-23 signaling, exhibit bias toward inducing Th2 response (Zhang et al, 2003). Dendritic cells (DCs) and macrophages are the two most important types of professional APCs, with similar functions and profiles of secreted cytokines (Lee et al, 2007;Saalmüller, 2006;Unanue, 1984).…”

“…Viability of the final APC population used for all experiments was >97% (data not shown). These MOG and/or M-CSFtreated APCs were washed and mixed with purified CD4 + or CD8 + T cells at a ratio of 1:1 as previously described (Zhang et al, 2003), and cultured at a final density of 2.0 × 10 6 /ml in RPMI 1640 supplemented with 10% FCS and 10 μg/ml of MOG . To determine APCdriven Tr differentiation, immunostaining for cell surface molecules and intracellular Foxp3 expression was carried out after 5 days of culture.…”

The secreted form of the p40 subunit of interleukin (IL)‐12 inhibits IL‐23 functions and abrogates IL‐23‐mediated antitumour effects

“…7,8 In contrast, several reports suggested a controversial role for IL-12 in the pathogenesis of EAE; p35-and IL-12Rb2-deficient mice still remained susceptible to EAE, whereas p40-and IL-12Rb1-deficient mice did not develop EAE. [9][10][11] A recent report showed that p19-deficient mice did not develop EAE, demonstrating that IL-23 rather than IL-12 was involved in the pathogenesis of EAE. 12 p40, the common subunit of IL-23 and IL-12, is experimentally secreted when neither p19 nor p35 is expressed, and can bind to IL-12Rb1, acting as an antagonist for IL-12; [13][14][15][16] thus, the production of p40 in vivo can be a novel self-regulatory process to suppress IL-12 functions.…”