title: Down-regulation of interleukin-2 production by CD4(+) T cells expressing TIM-3 through suppression of NFAT dephosphorylation and AP-1 transcription.
abstract: TIM-3 is expressed by TH1 cells and negatively regulates cytokine production by these cells. The aim of the present study was to explore the mechanisms by which IL-2 production is suppressed in TIM-3-expressing T cells. First, the activity of two transcription factors that bind to the IL-2 promoter was examined in Jurkat T cells expressing TIM-3. Both AP-1 and NFAT activity were reduced in TIM-3-expressing cells stimulated with a phorbol ester and a calcium ionophore. At the same time, expression of the AP-1 components, c-Fos and c-Jun, was induced to a lesser extent in stimulated human primary CD4(+) T cells expressing high levels of TIM-3 than in those expressing low levels of TIM-3. Furthermore, TIM-3-expression inhibited the stimulation-induced dephosphorylation and nuclear translocation of NFAT in Jurkat T cells and primary CD4(+) T cells. Finally, the cytoplasmic tail of TIM-3 was required for the suppression of IL-2 production and for AP-1 and NFAT activation. Taken together, these results suggest that IL-2 production by T cells may be downregulated by TIM-3-mediated signals, leading to suppression of NFAT dephosphorylation and AP-1 transcription.
authors.affiliation: Department of Microbiology, Ajou University School of Medicine, Youngtongku Wonchondong San 5, Suwon 442-749, Republic of Korea.
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Lee
authors.forename: Min-Yeong
authors.initials: MY
authors.lastname: Woo
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Chwae
authors.forename: Myung-Hee
authors.initials: MH
authors.lastname: Kwon
authors.forename: Kyongmin
authors.initials: K
authors.lastname: Kim
authors.forename: Sun
authors.initials: S
authors.lastname: Park
mesh_terms: D021581:Active Transport, Cell Nucleus; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007376:Interleukin-2; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D018808:Transcription Factor AP-1