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Resistance to Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis by Death Receptor 6-Deficient Mice

Clint S. Schmidt^1,2,*, Jingyong Zhao^1,*, Jana Chain^*, Deena Hepburn, Bruce Gitter, George Sandusky, Subba Chintalacharuvu^*, Andrew Glasebrook^* and Songqing Na^3,*

^* Stress and Immune Response, Neuroscience Research, and BioTechnology Discovery Research, Lilly Research Laboratories, Eli Lilly, Indianapolis, IN 46285

Genetic disruption of death receptor 6 (DR6) results in enhanced CD4⁺ T cell expansion, Th2 differentiation, and humoral responses after stimulation. However, the in vivo consequences of DR6 targeting (DR6^–/–) during the initiation and progression of inflammatory autoimmune disease are unclear. Using a myelin oligodendrocyte glycoprotein (MOG_35–55)-induced model of experimental autoimmune encephalomyelitis, DR6^–/– mice were found to be highly resistant to both the onset and the progression of CNS disease compared with wild-type (WT) littermates. DR6^–/– mice exhibited fewer inflammatory foci along with minimal demyelination and perivascular cuffing of inflammatory cells. Consistent with these observations, mononuclear cell infiltration, including CD4⁺ T cells and macrophages, in the spinal cord of DR6^–/– mice was dramatically reduced. Furthermore, CD4⁺ T cells from DR6^–/– mice exhibited profoundly reduced cell surface expression of VLA-4 before and after stimulation. Compared with WT mice, DR6^–/– mice exhibited significantly increased autoantigen-induced T cell proliferative responses along with greater numbers of IL-4-producing and similar or slightly higher numbers of IFN--producing CD4⁺ T cells. DR6^–/– CD4⁺ T cells secreted higher levels of the Th2 cytokine, IL-4, and similar levels of the Th1 cytokine, IFN-, compared with WT cells. Taken together, our data demonstrate that DR6 plays an important role in regulating leukocyte infiltration and function in the induction and progression of experimental autoimmune encephalomyelitis.