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* Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Department of Cell Therapy/Transplantation Medicine, University of Tokyo Hospital, Tokyo, Japan; and
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Notch signaling plays an important role during T cell development in the thymus and in T cell activation but the role of Notch in autoimmunity is not clear. We investigated the role of Jagged1 and Delta1 in experimental autoimmune encephalomyelitis. During experimental autoimmune encephalomyelitis, Delta1 expression is up-regulated on dendritic cells and B cells after priming while Jagged1 is up-regulated only on dendritic cells. Administration of anti-Jagged1 Ab exacerbated clinical disease while that of anti-Delta1 Ab reduced the severity of the clinical disease. In contrast, administration of Jagged1-Fc protected from disease, that of Delta1-Fc exacerbated disease. Treatment with Jagged1-Fc was associated with increased IL-10-producing Ag-specific cells in the CNS, while anti-Jagged1 decreased the frequency of IL-10-producing cells. Treatment with Delta1-Fc increased Th1 cells in the CNS, while anti-Delta-1 decreased the frequency of Th1 cells. Manipulation of Delta1 or Jagged1 had no effect on the frequency of Th17 cells or FoxP3+ cells. Moreover, Jagged1 may play a role in CNS homeostasis because murine astrocytes specifically express Jagged1 that is up-regulated by TGF-
, whereas IFN-
, TNF-
, and IL-17 decrease Jagged1 expression. Our study provides novel data about differential roles of Notch ligands in regulating inflammation in the periphery as well as in the CNS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by research grants from the National Multiple Sclerosis Society (RG3666, RG2988; to S.J.K.) and the National Institutes of Health (AI058680 and AI043496; to S.J.K.). W.E. is a recipient of a National Research Service Award fellowship from the National Institute of Neurological Disorders and Stroke (F32 F32 NS059205-01A1). E.M.B. is a recipient of a National Research Service Award fellowship from the National Institute of Allergy and Infectious Diseases (F32AI065100-01A1).
2 Address correspondence and reprint requests to Dr. Samia J. Khoury, Center for Neurologic Diseases, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, Room 712, Boston, MA 02115. E-mail address: skhoury{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: IC, intracellular; DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; Treg, regulatory T cell; MOG, myelin oligodendrocyte glycoprotein; GFAP, glial fibrillary acidic protein; RT, reverse transcription; MS, multiple sclerosis; LCM, laser capture microdissection; RBP, recombination signal sequence-binding protein; CSL, Cp-binding protein/RBP-J
/suppressor of hairless/LAG-1.
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