Resistance to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis by death receptor 6-deficient mice.
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-gamma-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-gamma, 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.
Schmidt
Clint S
CS
Stress and Immune Response, Lilly Research Laboratories, Eli Lilly, Indianapolis, IN 46285, USA.
Zhao
Jingyong
J
Chain
Jana
J
Hepburn
Deena
D
Gitter
Bruce
B
Sandusky
George
G
Chintalacharuvu
Subba
S
Glasebrook
Andrew
A
Na
Songqing
S
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage* / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D007116:Immunization, Passive; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D039041:Integrin alpha4beta1; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D015847:Interleukin-4