title: Notch signalling suppresses regulatory T-cell function in murine experimental autoimmune uveitis.
abstract: Autoimmune uveitis is an intraocular inflammatory disorder in developed countries. Understanding the mechanisms underlying the development and modulation of immune reaction in uveitic eyes is critical for designing therapeutic interventions. Here we investigated the role of Notch signalling in regulatory T-cell (Treg cell) function during experimental autoimmune uveitis (EAU). Using the Foxp3-GFP reporter mouse strain, the significance of Notch signalling for the function of infiltrating Treg cells was characterized in an EAU model. We found that infiltrating Treg cells substantially expressed Notch-1, Notch-2, JAG1 and DLL1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES1 and HES5, was enhanced in infiltrating Treg cells. Treatment with JAG1 and DLL1 down-regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro, whereas neutralizing antibodies against JAG1 and DLL1 diminished Notch ligand-mediated negative effects on Treg cells. To investigate the significance of Notch signalling for Treg cell function in vivo, lentivirus-derived Notch short hairpin RNAs were transduced into in vitro expanded Treg cells before adoptive transfer of Treg cells into EAU mice. Transfer of Notch-1-deficient Treg cells remarkably reduced pro-inflammatory cytokine production and inflammatory cell infiltration in uveitic eyes. Taken together, Notch signalling negatively modulates the immunosuppressive function of infiltrating Treg cells in mouse EAU.
authors: Department of Ophthalmology, Shanghai Construction Group Hospital, Shanghai, China.|Tongji University School of Medicine, Shanghai, China.
authors: Hua
authors: H
authors: Rong
authors: Department of Ophthalmology, Jinshan Hospital, Fudan University School of Medicine, Shanghai, China.
authors: Hongjie
authors: H
authors: Shen
authors: Department of Ophthalmology, East Hospital, Tongji University School of Medicine, Shanghai, China.
authors: Yueli
authors: Y
authors: Xu
authors: Department of Ophthalmology, East Hospital, Tongji University School of Medicine, Shanghai, China. datouyh@126.com.
authors: Hai
authors: H
authors: Yang
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology*; D002135:Calcium-Binding Proteins; D002478:Cells, Cultured; D006801:Humans; D056747:Immunomodulation; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D058990:Molecular Targeted Therapy; D034741:RNA, Small Interfering / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D014605:Uveitis / Q000188:drug therapy / Q000276:immunology*
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D034741:RNA, Small Interfering; D051881:Receptor, Notch1; D051883:Receptor, Notch2
keywords: Delta-like ligand 1; Jagged 1; Notch; experimental autoimmune uveitis; regulatory T cells