title: Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse.
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.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
authors.forename: Donghee
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Life Science, Gachon University, Seongnam, Gyeonggi-Do, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.|College of Pharmacy and Gachon Institute Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.|Gil Medical Research Institute, Gil Hospital, Incheon, Republic of Korea.
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000367:Age Factors; D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D009301:Nasolacrimal Duct / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D012469:Salivary Glands / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D012472:Salivation; D015398:Signal Transduction; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C000611649:IFNG protein, mouse; D020381:Interleukin-17; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D007371:Interferon-gamma
keywords: IL-17; Immune response; Immunity; Immunology and Microbiology Section; NOD mice; Sjögren’s syndrome; Smad4; TGF-beta