Abstract
The MOG35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice is a useful animal model to explore therapeutic approaches to T cell-mediated autoimmune diseases because the dominant T-cell epitope(s) have been defined. It is rational that antigen-specific immunosuppression can be induced by using MHC-peptide complexes as specific TCR ligand(s) that interact with autoreactive T cells in the absence of co-stimulation. In this study, a soluble divalent MOG35-55/I-Ab fusion protein (MOG35-55/I-Ab dimer) was constructed to specifically target the autoreactive CD4+ T cells in the EAE mouse. Intraperitoneal administration of the MOG35-55/I-Ab dimer significantly delayed and ameliorated EAE symptoms by reducing EAE-related inflammation in the mouse CNS and reducing encephalitogenic Th1 and Th17 cells in the peripheral lymphoid organs. We observed that dimer intervention at a concentration of 1.2 nM suppressed MOG35-55 peptide-specific 2D2 transgenic T cells (2D2 T cells) proliferation by over 90% after in vitro activation with MOG35-55 peptide. The mechanisms involved in this antigen-specific dimer-mediated suppression were found to be downregulated TCR-CD3 expression as well as upregulated expression of membrane-bound TGF-β (mTGF-β) and IL-10 suppressive cytokines by the autoreactive CD4+ T cells. Collectively, our data demonstrates that soluble divalent MHC class II molecules can abrogate pathogenic T cells in EAE. Furthermore, our data suggests that this strategy may provide an efficient and clinically useful option to treat autoimmune diseases.
Highlights
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases mediated by myelin-reactive CD4+ T cells targeting myelinproducing cells of the CNS [1]
I-Ab dimers loaded with I-Ab-restricted peptides, biotinylated-MOG35-55 as well as biotinylated-Mulv env145–158, were reactive to HRPlabeled streptavidin, suggesting these peptides can be effectively loaded onto I-Ab dimers (Fig. S1E)
Using the MOG35-55 peptide-induced EAE model in C57BL/ 6 mice, our study showed that the MOG35-55/I-Ab dimer can inhibit autoreactive T-cell expansion, reduce inflammation in CNS, and ameliorate clinical signs of EAE
Summary
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are autoimmune diseases mediated by myelin-reactive CD4+ T cells targeting myelinproducing cells of the CNS [1]. EAE can be induced in genetically susceptible mouse strains by immunization with myelin antigens, including myelin basis protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). MOG35-55 peptide is the major immunodominant epitope of MOG; it has been identified as an agonist of encephalitogenic T cells in the C57BL/6 mouse model [5]. MOG35-55 peptide-induced EAE in the C57BL/6 mouse serves as an animal model to explore therapeutic approaches to the MS, and the transgenic 2D2 mouse of a C57BL/6 background expressing Va3.2/Vb11 TCR with specificity for MOG35-55 peptide facilitates this exploration [6]
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