ABSTRACT
Macrophages act as the first line of self defense by mounting an inflammatory response to antigen and as antigen presenting cells to initiate the adaptive immune response. Inhibition of macrophage activation is one of the possible approaches to modulate inflammation. Intravenous (i.v.) tolerance has proved to be an effective method for ameliorating experimental autoimmune diseases. Whether macrophages are involved in tolerance induction is still largely undefined. In the present study we found that i.v. tolerance induction resulted in lower B7.1, B7.2 and MHC class II molecules, and reduced phagocytosis by both peritoneal macrophages and adherent splenocytes. Macrophages from tolerized mice were associated with a significantly impaired response of MOG-sensitized T cells to MOG. Macrophages from tolerized mice produced low levels of pro-inflammatory molecules IL-12, TNF-alpha, IL-1beta, RANTES and MCP-1 and high levels of IL-10 and TGF-beta. Administration of anti-TGF-beta led to a reduction of IL-10 in tolerized mice. Thus, i.v. tolerance inhibits macrophage classical activation and APC function, increases macrophage alternative activation and IL-10 and TGF-beta production. These cytokines, in turn, induce enhanced production of IL-10 in macrophages in MOG i.v. mice.
Subject(s)
Antigen Presentation/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Immune Tolerance , Macrophage Activation/immunology , Animals , Autoantigens/administration & dosage , Autoantigens/immunology , Autoantigens/metabolism , Cells, Cultured , Coculture Techniques , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Glycoproteins/administration & dosage , Glycoproteins/immunology , Injections, Intravenous , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein , Peptide Fragments/administration & dosage , Peptide Fragments/immunologyABSTRACT
We have previously shown that mice lacking the IL-12-specific receptor subunit beta2 (IL-12Rbeta2) develop more severe experimental autoimmune encephalomyelitis than wild-type (WT) mice. The mechanism underlying this phenomenon is not known; nor is it known whether deficiency of IL-12Rbeta2 impacts other autoimmune disorders similarly. In the present study we demonstrate that IL-12Rbeta2(-/-) mice develop earlier onset and more severe disease in the streptozotocin-induced model of diabetes, indicating predisposition of IL-12Rbeta2-deficient mice to autoimmune diseases. T cells from IL-12Rbeta2(-/-) mice exhibited significantly higher proliferative responses upon TCR stimulation. The numbers of naturally occurring CD25(+)CD4(+) regulatory T cells (Tregs) in the thymus and spleen of IL-12Rbeta2(-/-) mice were comparable to those of WT mice. However, IL-12Rbeta2(-/-) mice exhibited a significantly reduced capacity to develop Tregs upon stimulation with TGF-beta, as shown by significantly lower numbers of CD25(+)CD4(+) T cells that expressed Foxp3. Functionally, CD25(+)CD4(+) Tregs derived from IL-12Rbeta2(-/-) mice were less efficient than those from WT mice in suppressing effector T cells. The role of IL-12Rbeta2 in the induction of Tregs was confirmed using small interfering RNA. These findings suggest that signaling via IL-12Rbeta2 regulates both the number and functional maturity of Treg cells, which indicates a novel mechanism underlying the regulation of autoimmune diseases by the IL-12 pathway.
