title: Aire-Overexpressing Dendritic Cells Induce Peripheral CD4⁺ T Cell Tolerance.
abstract: Autoimmune regulator (Aire) can promote the ectopic expression of peripheral tissue-restricted antigens (TRAs) in thymic medullary epithelial cells (mTECs), which leads to the deletion of autoreactive T cells and consequently prevents autoimmune diseases. However, the functions of Aire in the periphery, such as in dendritic cells (DCs), remain unclear. This study's aim was to investigate the effect of Aire-overexpressing DCs (Aire cells) on the functions of CD4⁺ T cells and the treatment of type 1 diabetes (T1D). We demonstrated that Aire cells upregulated the mRNA levels of the tolerance-related molecules CD73, Lag3, and FR4 and the apoptosis of CD4⁺ T cells in STZ-T1D mouse-derived splenocytes. Furthermore, following insulin stimulation, Aire cells decreased the number of CD4⁺ IFN-γ⁺ T cells in both STZ-T1D and WT mouse-derived splenocytes and reduced the expression levels of TCR signaling molecules (Ca(2+) and p-ERK) in CD4⁺ T cells. We observed that Aire cells-induced CD4⁺ T cells could delay the development of T1D. In summary, Aire-expressing DCs inhibited TCR signaling pathways and decreased the quantity of CD4⁺IFN-γ⁺ autoreactive T cells. These data suggest a mechanism for Aire in the maintenance of peripheral immune tolerance and provide a potential method to control autoimmunity by targeting Aire.
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. lidongbei2008@163.com.
authors.forename: Dongbei
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. 13944883280@163.com.
authors.forename: Haijun
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. fuhy@jlu.edu.cn.
authors.forename: Haiying
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. niukw123@163.com.
authors.forename: Kunwei
authors.initials: K
authors.lastname: Niu
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. gb123450000@163.com.
authors.forename: Yantong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. guochuanxy@163.com.
authors.forename: Chuan
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. sjitong@163.com.
authors.forename: Jitong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. liyi@jlu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Norman Bethune College of Medicine, Jilin University, Changchun 130021, China. ywei@jlu.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D007108:Immune Tolerance; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein; D000096927:AIRE Protein
chemical_list: D015720:5'-Nucleotidase; D015703:Antigens, CD; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000093322:Lymphocyte Activation Gene 3 Protein; D000096927:AIRE Protein; C543634:folate receptor 4, mouse; C000720327:Lag3 protein, mouse
keywords: Aire; CD4+T cells; DCs; T1D