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Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis
Author(s) -
Rong Hua,
Shen Hongjie,
Xu Yueli,
Yang Hai
Publication year - 2016
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12663
Subject(s) - notch signaling pathway , hes1 , foxp3 , jag1 , immunology , adoptive cell transfer , uveitis , microbiology and biotechnology , immune system , biology , t cell , signal transduction
Summary 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, JAG 1 and DLL 1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES 1 and HES 5, was enhanced in infiltrating Treg cells. Treatment with JAG 1 and DLL 1 down‐regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro , whereas neutralizing antibodies against JAG 1 and DLL 1 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 RNA s 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 .