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James Sampson, Amol Suryawanshi, Wei-Sheng Chen, Lama Mulki, Eiichi Hasegawa, Kip M Connor, Gabriel A Rabinovich, Noorjahan A Panjwani; Galectin-8 inhibits experimental autoimmune uveitis by promoting regulatory T cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4601.
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© ARVO (1962-2015); The Authors (2016-present)
Galectins (gal) such as gal-1 and gal-9 have been shown to play an immunomodulatory role by inhibiting effector T cells and promoting regulatory T cells (Treg), however the role of gal-8 in T cell homeostasis is poorly understood. Experimental autoimmune uveitis (EAU) is a mouse model of uveitis that is driven by Th17 cells. Pathology can be ameliorated by shifting the T cell response from Th17 to Treg. Thus, the purpose of this study is to determine what role gal-8 plays in T cell differentiation, and to determine whether gal-8 treatment reduces EAU pathology.
Mouse CD4+ T cells were isolated by negative selection and polarized to Th1, Th2, Th17, and Treg in the presence and absence of recombinant gal-8 to determine the effects of gal-8 on T cell differentiation. In order to identify novel gal-8 binding partners, the effects of gal-8 on IL-2 receptor and TGFβ receptor signaling, necessary for Treg polarization, were determined by western blotting. The ability of Tregs to inhibit proliferation of activated T cells was assessed in in vitro suppression assays. EAU was actively induced by immunization with IRBP1-20, and one group of mice were treated with vehicle, while the other group was treated with gal-8.
Recombinant gal-8 promoted Th2 and Treg differentiation and induced apoptosis of Th17 cells in vitro. Gal-8 sustained STAT5 phosphorylation downstream of IL-2 receptor, and enhanced Smad3 phosphorylation downstream of TGFβ receptor to promote Treg polarization. Tregs polarized in the presence of gal-8 suppressed division of activated T cells. Treatment of uveitic mice with gal-8 resulted in significantly delayed pathology and expanded Tregs in draining lymph nodes.
Gal-8 induces apoptosis of Th17 cells and promotes Treg differentiation, making it a good candidate for treating human uveitis without the side effects of long-term corticosteroids or immunosuppressive drugs.
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