title: The Tim-3/galectin-9 pathway involves in the homeostasis of hepatic Tregs in a mouse model of concanavalin A-induced hepatitis.
abstract: T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) is a negative regulator of interferon (IFN)-γ-secreting CD4(+) Th1 cells and plays a key role in autoimmune diseases. Here, we report that galectin-9 expression was increased in hepatic CD4(+)CD25(+) T cells in a mouse model of concanavalin A (Con A)-induced hepatitis. Moreover, Tim-3 showed increased levels in CD4(+)CD25(+) Foxp3(+) regulatory T cells (Tregs). Further analyses showed that blocking the Tim-3/galectin-9 pathway resulted in the suppression of Tregs in vitro, thereby significantly increasing interferon (IFN)-γ production from hepatic Teffs. Moreover, blockade of Tim-3 in vivo with an anti-Tim-3 antibody exacerbated the acute hepatitis, possibly by increased IFN-γ production. Furthermore, we found that in vitro activation of CD4(+)CD25(-) T cells with the T cell receptor (TCR) plus interleukin 2 (IL-2) up-regulated Tim-3 expression. And the induced Tim-3 interacted with galectin-9 to induce CD4(+) T cell apoptosis which could be partly reversed by blocking Tim-3 signaling. Our results suggested that the Tim-3/galectin-9 pathway plays a critical role in the homeostasis of hepatic Tregs through the elimination induction in Teffs and the inhibition of IFN-γ release, which contributes to the pathogenesis of liver damage and constitutes at least part of the mechanism underlying the induction of hepatitis by Con A.
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Ying
authors: Y
authors: Ju
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Xuming
authors: X
authors: Shang
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Zhanfeng
authors: Z
authors: Liu
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Ji
authors: J
authors: Zhang
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Yuantang
authors: Y
authors: Li
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Yajuan
authors: Y
authors: Shen
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Yiqing
authors: Y
authors: Liu
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Chunmei
authors: C
authors: Liu
authors: Department of Center Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Bin
authors: B
authors: Liu
authors: Cell and Molecular Biology Laboratory, Hospital of Zhoushan, Zhoushan, Zhejiang 316000, PR China.
authors: Liyun
authors: L
authors: Xu
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China.
authors: Yong
authors: Y
authors: Wang
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China. Electronic address: zhangbingchangb@163.com.
authors: Bingchang
authors: B
authors: Zhang
authors: Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, PR China. Electronic address: zoujianwen36@163.com.
authors: Jianwen
authors: J
authors: Zou
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D037161:Galectins / Q000276:immunology*; D006505:Hepatitis / Q000276:immunology*; D000072597:Hepatitis A Virus Cellular Receptor 2; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011991:Receptors, Virus / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
chemical_list: D019138:Antibodies, Blocking; D015704:CD4 Antigens; D003208:Concanavalin A; D051858:Forkhead Transcription Factors; D037161:Galectins; D000072597:Hepatitis A Virus Cellular Receptor 2; D007371:Interferon-gamma; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D011991:Receptors, Virus; C498833:Foxp3 protein, mouse; C442241:Havcr2 protein, mouse; C508186:galectin 9, mouse
keywords: ALT; AST; Con A; Concanavalin A; Effector T cells; HBV; HMCs; Homeostasis; IFN-γ; IL-10; IL-2; PBMCs; Regulatory T cells; T cell immunoglobulin- and mucin-domain-containing molecule-3; T cell receptor; TCR; TGF-β; TNF-α; Teffs; Tim-3; Tregs; aGVHD; acute graft-versus-host disease; alanine aminotransferase; aspartate transaminase; concanavalin A; effector T cells; hepatic mononuclear cells; hepatitis B virus; interferon-γ; interleukin 10; interleukin 2; peripheral blood mononuclear cells; qPCR; quantitative real-time PCR; regulatory T cells; transforming growth factor; tumor necrosis factor-α