title: DNA demethylation of the TIM-3 promoter is critical for its stable expression on T cells.
abstract: The T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is selectively expressed on terminally differentiated T helper 1 (Th1) cells and acts as a negative regulator that terminates Th1 responses. The dysregulation of TIM-3 expression on T cells is associated with several autoimmune phenotypes and with chronic viral infections; however, the mechanism of this regulation is unclear. In this study, we investigated the effect of DNA methylation on the expression of TIM-3. By analyzing the sequences of TIM-3 promoter regions in human and mouse, we identified a CpG island within the TIM-3 promoter and demonstrated that the promoter activity was controlled by DNA methylation. Furthermore, treatment with 5-aza-2'-deoxycytidine enhanced TIM-3 expression on mouse primary CD4(+) T cells under Th0-, Th1- or Th2-polarizing conditions. Finally, pyrosequencing analysis revealed that the methylation level of the TIM-3 promoter gradually decreased after each round of T-cell polarization, and this decrease was inversely correlated with TIM-3 expression. These data suggest that the DNA methylation of the TIM-3 promoter cooperates with lineage-specific transcription factors in the control of Th-cell development. In conclusion, DNA methylation-based regulation of TIM-3 may provide novel insights into understanding the dysregulation of TIM-3 expression under pathogenic conditions.
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: F-C
authors.initials: FC
authors.lastname: Chou
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.
authors.forename: C-C
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
authors.forename: H-H
authors.initials: HH
authors.lastname: Chen
authors.affiliation: Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan.|Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: H-K
authors.initials: HK
authors.lastname: Sytwu
mesh_terms: D000818:Animals; D019070:Cell Lineage; D018899:CpG Islands; D019175:DNA Methylation; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D011401:Promoter Regions, Genetic; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D014157:Transcription Factors