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DNA demethylation of the TIM-3 promoter is critical for its stable expression on T cells

Genes & Immunity volume 17, pages 179–186 (2016)Cite this article

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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.

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Acknowledgements

This work was supported by the Ministry of Science and Technology, Taiwan, ROC (MOST 103-2320-B-016-017-MY3 and MOST 104-2320-B-016-014-MY3 to H-KS; NSC 102-2321-B-016-005-MY3 to F-CC), and Tri-service General Hospital foundation (TSGH-C103-005-007-009-S01 and TSGH-C104-008-S02 to H-KS). We thank Drs Maja Klug and Michael Rehli for kindly providing us the CpG-free plasmids.

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Authors and Affiliations

  1. Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Taipei, Taiwan

    F-C Chou, C-C Kuo & H-K Sytwu

  2. Graduate Institutes of Life Sciences, National Defense Medical Center, Taipei, Taiwan

    H-Y Chen & H-K Sytwu

  3. Department of Medicine, National Defense Medical Center, Taipei, Taiwan

    H-H Chen

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Chou, FC., Kuo, CC., Chen, HY. et al. DNA demethylation of the TIM-3 promoter is critical for its stable expression on T cells. Genes Immun 17, 179–186 (2016). https://doi.org/10.1038/gene.2016.6

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