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Distinct Methylation of the Interferon (IFN-) and Interleukin 3 (IL-3) Genes in Newly Activated Primary CD8⁺ T Lymphocytes: Regional IFN- Promoter Demethylation and mRNA Expression Are Heritable in CD44^highCD8⁺ T Cells

David R. Fitzpatrick^*, Kym M. Shirley^*, Louise E. McDonald, Helle Bielefeldt-Ohmann, Graham F. Kay, and Anne Kelso^*

From the ^* Leukocyte Biology Unit and the Cancer Research Unit, The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Queensland 4029, Australia; and the Department of Microbiology, University of Queensland, St. Lucia, Queensland 4072, Australia

Differential genomic DNA methylation has the potential to influence the development of T cell cytokine production profiles. Therefore, we have conducted a clonal analysis of interferon (IFN)- and interleukin (IL)-3 gene methylation and messenger (m)RNA expression in primary CD8⁺ T cells during the early stages of activation, growth, and cytokine expression. Despite similar distributions and densities of CpG methylation sites, the IFN- and IL-3 promoters exhibited differential demethylation in the same T cell clone, and heterogeneity between clones. Methylation patterns and mRNA levels were correlated for both genes, but demethylation of the IFN- promoter was widespread across >300 basepairs in clones expressing high levels of IFN- mRNA, whereas demethylation of the IL-3 promoter was confined to specific CpG sites in the same clones. Conversely, the majority of clones expressing low or undetectable levels of IFN- mRNA exhibited symmetrical methylation of four to six of the IFN- promoter CpG sites. Genomic DNA methylation also has the potential to influence the maintenance or stability of T cell cytokine production profiles. Therefore, we also tested the heritability of IFN- gene methylation and mRNA expression in families of clones derived from resting CD44^lowCD8⁺ T cells or from previously activated CD44^highCD8⁺ T cells. The patterns of IFN- gene demethylation and mRNA expression were faithfully inherited in all clones derived from CD44^high cells, but variable in clones derived from CD44^low cells. Overall, these findings suggest that differential genomic DNA methylation, including differences among cytokine genes, among individual T cells, and among T cells with different activation histories, is an important feature of cytokine gene expression in primary T cells.

Key Words: interferon • interleukin • CD8⁺ T cell • DNA methylation • gene expression

Abbreviations used: AP, activator protein; ATF, activating transcription factor; CREB, cyclic AMP response element binding protein; QCPCR, quantitative competitive PCR.

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• Zhu, X., Deng, C., Kuick, R., Yung, R., Lamb, B., Neel, J. V., Richardson, B., Hanash, S. (1999). Analysis of human peripheral blood T cells and single-cell-derived T cell clones uncovers extensive clonal CpG island methylation heterogeneity throughout the genome. Proc. Natl. Acad. Sci. USA 96: 8058-8063 [Abstract] [Full Text]  
• Biedermann, B. C., Pober, J. S. (1999). Human Vascular Endothelial Cells Favor Clonal Expansion of Unusual Alloreactive CTL. J. Immunol. 162: 7022-7030 [Abstract] [Full Text]  
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