Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse.

Donghee Kim,Jae Young Kim,Hee-Sook Jun

doi:10.18632/oncotarget.13437

Donghee Kim, Jae Young Kim + Show 1 more

Open Access

https://doi.org/10.18632/oncotarget.13437

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Journal: Oncotarget	Publication Date: Nov 17, 2016
Citations: 5	License type: cc-by

Affiliation: Gachon University, Gachon University Gil Hospital

Abstract

We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjögren's syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4fl/fl,CD4-Cre; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4+/+,CD4-Cre; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age. Activated/memory T cells and cytokine (IFN-γ, IL-17)-producing T cells were increased in Smad4 tKO NOD mice, however the proportion and function of regulatory T (Treg) cells were not different between Smad4 tKO and WT NOD mice. Effector T (Teff) cells from Smad4 tKO NOD mice were less sensitive than WT Teff cells to suppression by Treg cells. Th17 differentiation capability of Teff cells was similar between Smad4 tKO and WT NOD mice, but IL-17 expression was increased under inducible Treg skewing conditions in T cells from Smad4 tKO NOD mice. Our results demonstrate that disruption of the Smad4 pathway in T cells of NOD mice increases Teff cell activation resulting in upregulation of Th17 cells, indicating that Smad4 in T cells has a protective role in the development of SS in NOD mice.

Highlights

Sjögren’s syndrome (SS) is a systemic chronic autoimmune disease that targets the exocrine glands, predominantly the salivary glands and lacrimal glands, resulting in xerostomia and keratoconjunctivitis sicca [1]
We confirmed the absence of Smad4 mRNA (Figure 1A) and protein (Figure 1B) expression in T cells from Smad4 tKO nonobese diabetic (NOD) compared with WT NOD mice
Cellular infiltration of the lacrimal glands is delayed in female mice; a study showed that ~25% of male lacrimal glands are infiltrated at 12 weeks of age, whereas age-matched female NOD mice still lack major signs of inflammation [22]

Summary

Introduction

Sjögren’s syndrome (SS) is a systemic chronic autoimmune disease that targets the exocrine glands, predominantly the salivary glands and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) [1]. A focal lymphocytic infiltration of mainly CD4+ T cells is found in these glands in affected individuals [2, 3]. The nonobese diabetic (NOD) mouse is commonly used as a model of SS and spontaneously develops lymphocytic infiltration in exocrine glands with corresponding loss of secretory function [1]. Binding of TGF-β to TGFβRI leads to phosphorylation of the signal transducers Smad and Smad, which form a complex with Smad and translocate into the nucleus [6]. TGF-β has inhibitory effects on T cell and B cell proliferation, induces regulatory T cell differentiation and function [7, 8] and is important for the induction of Th17 cells [9, 10]

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