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Identification of DNA Methyltransferase 3a as a T Cell Receptor-Induced Regulator of Th1 and Th2 Differentiation
Abstract
Ag-specific T cell cytokine expression is dictated by the context in which TCR engagement occurs. Recently it has become clear that epigenetic changes play a role in this process. DNA methyltransferase 3a (DNMT3a) is a de novo methyltransferase important to the epigenetic control of cell fate. We have determined that DNMT3a expression is increased following TCR engagement and that costimulation mitigates DNMT3a protein expression. T cells lacking DNMT3a simultaneously express IFN-γ and IL-4 after expansion under nonbiasing conditions. While global methylation of DNA from wild-type and knockout T cells is similar, DNMT3a-null T cells demonstrate selective hypomethylation of both the Il4 and Ifng loci after activation. Such hypomethylated knockout Th2 cells retain a greater capacity to express IFN-γ protein when they are subsequently exposed to Th1-biasing conditions. Based on these findings we propose that DNMT3a is a key participant in regulating T cell polarization at the molecular level by promoting stable selection of a context-specific cell fate through methylation of selective targets in T cells.
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“Similarly, DNMT3A localization to the Ifng promoter in T helper 2 (T H 2) cells, T helper 17 (T H 17) cells and regulatory T (T reg ) cells generated in vitro is associated with increased methylation and reduced Ifng expression; reduced Ifng methylation in DNMT3A-deficient T H 2, T H 17 and T reg cells leads to aberrant IFNγ production by all three subsets upon restimulation with the T H 1 cytok”
From Clonal haematopoiesis and dysregulation of the immune system (2023) · cites this paper as [167]
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Cites
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Cited by
Franke, A., McGovern, D. P. B., Barrett, J. C., Wang, K., Radford-Smith, G. L., Ahmad, T., Lees, C. W., Balschun, T., Lee, J., Roberts, R., et al. (2010) · Nature Genetics · doi:10.1038/ng.717 · Cited by 2,520
Role of donor clonal hematopoiesis in allogeneic hematopoietic stem-cell transplantation
Frick, M., Chan, W., Arends, C. M., Hablesreiter, R., Halik, A., Heuser, M., Michonneau, D., Blau, O., Hoyer, K., Christen, F., et al. (2019) · Journal of Clinical Oncology · doi:10.1200/jco.2018.79.2184 · Cited by 223
Clonal haematopoiesis and dysregulation of the immune system
Belizaire, R., Wong, W. J., Robinette, M. L., & Ebert, B. L. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00843-3 · Cited by 161
Ladle, B. H., Li, K.-P., Phillips, M. J., Pucsek, A. B., Haile, A., Powell, J. D., Jaffee, E. M., Hildeman, D. A., & Gamper, C. J. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1524490113 · Cited by 152
Self-citationDnmt3a restrains mast cell inflammatory responses
Leoni, C., Montagner, S., Rinaldi, A., Bertoni, F., Polletti, S., Balestrieri, C., & Monticelli, S. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1616420114 · Cited by 138
Metadata
- Authors
- Gamper, C. J., Agoston, A. T., Nelson, W. G., & Powell, J. D.
- Affiliations
- Department of Oncology, Johns Hopkins University, School of Medicine , Baltimore, MD 21231
- Department of Pathology, Brigham and Women’s Hospital , Boston, MA 02115
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-08
- Volume
- 183
- Issue
- 4
- Pages
- 2267-2276
- ISSN
- 1550-6606
- 0022-1767
- PMC
- PMC2818975
- Cited by
- 100
- References
- 1
- Language
- en
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- Gamper, C. J., Agoston, A. T., Nelson, W. G., & Powell, J. D. (2009). Identification of DNA Methyltransferase 3a as a T Cell Receptor-Induced Regulator of Th1 and Th2 Differentiation. The Journal of Immunology. https://doi.org/10.4049/jimmunol.0802960
