J. Exp. Med., Volume 188, Number 1, July 1, 1998 103-117

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

By 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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Samten, B., Townsend, J. C., Weis, S. E., Bhoumik, A., Klucar, P., Shams, H., Barnes, P. F. (2008). CREB, ATF, and AP-1 Transcription Factors Regulate IFN-{gamma} Secretion by Human T Cells in Response to Mycobacterial Antigen. J. Immunol. 181: 2056-2064 [Abstract] [Full Text]  
• Dong, J., Ivascu, C., Chang, H.-D., Wu, P., Angeli, R., Maggi, L., Eckhardt, F., Tykocinski, L., Haefliger, C., Mowes, B., Sieper, J., Radbruch, A., Annunziato, F., Thiel, A. (2007). IL-10 Is Excluded from the Functional Cytokine Memory of Human CD4+ Memory T Lymphocytes. J. Immunol. 179: 2389-2396 [Abstract] [Full Text]  
• Northrop, J. K., Thomas, R. M., Wells, A. D., Shen, H. (2006). Epigenetic Remodeling of the IL-2 and IFN-{gamma} Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells. J. Immunol. 177: 1062-1069 [Abstract] [Full Text]  
• Chappell, C., Beard, C., Altman, J., Jaenisch, R., Jacob, J. (2006). DNA methylation by DNA methyltransferase 1 is critical for effector CD8 T cell expansion.. J. Immunol. 176: 4562-4572 [Abstract] [Full Text]  
• Kersh, E. N., Fitzpatrick, D. R., Murali-Krishna, K., Shires, J., Speck, S. H., Boss, J. M., Ahmed, R. (2006). Rapid Demethylation of the IFN-{gamma} Gene Occurs in Memory but Not Naive CD8 T Cells. J. Immunol. 176: 4083-4093 [Abstract] [Full Text]  
• Ueda, Y., Okano, M., Williams, C., Chen, T., Georgopoulos, K., Li, E. (2006). Roles for Dnmt3b in mammalian development: a mouse model for the ICF syndrome.. Development 133: 1183-1192 [Abstract] [Full Text]  
• Olver, S., Groves, P., Buttigieg, K., Morris, E. S., Janas, M. L., Kelso, A., Kienzle, N. (2006). Tumor-Derived Interleukin-4 Reduces Tumor Clearance and Deviates the Cytokine and Granzyme Profile of Tumor-Induced CD8+ T Cells. Cancer Res. 66: 571-580 [Abstract] [Full Text]  
• Bonilla-Henao, V., Martinez, R., Sobrino, F., Pintado, E. (2005). Different signaling pathways inhibit DNA methylation activity and up-regulate IFN-{gamma} in human lymphocytes. J. Leukoc. Biol. 78: 1339-1346 [Abstract] [Full Text]  
• Tong, Y., Aune, T., Boothby, M. (2005). T-bet antagonizes mSin3a recruitment and transactivates a fully methylated IFN-{gamma} promoter via a conserved T-box half-site. Proc. Natl. Acad. Sci. USA 102: 2034-2039 [Abstract] [Full Text]  
• Winders, B. R., Schwartz, R. H., Bruniquel, D. (2004). A Distinct Region of the Murine IFN-{gamma} Promoter Is Hypomethylated from Early T Cell Development through Mature Naive and Th1 Cell Differentiation, but Is Hypermethylated in Th2 Cells. J. Immunol. 173: 7377-7384 [Abstract] [Full Text]  
• Makar, K. W., Wilson, C. B. (2004). DNA Methylation Is a Nonredundant Repressor of the Th2 Effector Program. J. Immunol. 173: 4402-4406 [Abstract] [Full Text]  
• Yano, S., Ghosh, P., Kusaba, H., Buchholz, M., Longo, D. L. (2003). Effect of Promoter Methylation on the Regulation of IFN-{gamma} Gene During In Vitro Differentiation of Human Peripheral Blood T Cells into a Th2 Population. J. Immunol. 171: 2510-2516 [Abstract] [Full Text]  
• Vigneau, S., Rohrlich, P.-S., Brahic, M., Bureau, J.-F. (2003). Tmevpg1, a Candidate Gene for the Control of Theiler's Virus Persistence, Could Be Implicated in the Regulation of Gamma Interferon. J. Virol. 77: 5632-5638 [Abstract] [Full Text]  
• Johnson, B. J., Costelloe, E. O., Fitzpatrick, D. R., Haanen, J. B. A. G., Schumacher, T. N. M., Brown, L. E., Kelso, A. (2003). Single-cell perforin and granzyme expression reveals the anatomical localization of effector CD8+ T cells in influenza virus-infected mice. Proc. Natl. Acad. Sci. USA 100: 2657-2662 [Abstract] [Full Text]  
• Walzer, T., Marcais, A., Saltel, F., Bella, C., Jurdic, P., Marvel, J. (2003). Cutting Edge: Immediate RANTES Secretion by Resting Memory CD8 T Cells Following Antigenic Stimulation. J. Immunol. 170: 1615-1619 [Abstract] [Full Text]  
• Chan, H.-W., Kurago, Z. B., Stewart, C. A., Wilson, M. J., Martin, M. P., Mace, B. E., Carrington, M., Trowsdale, J., Lutz, C. T. (2003). DNA Methylation Maintains Allele-specific KIR Gene Expression in Human Natural Killer Cells. J. Exp. Med. 197: 245-255 [Abstract] [Full Text]  
• Santangelo, S., Cousins, D. J., Winkelmann, N. E. E., Staynov, D. Z. (2002). DNA Methylation Changes at Human Th2 Cytokine Genes Coincide with DNase I Hypersensitive Site Formation During CD4+ T Cell Differentiation. J. Immunol. 169: 1893-1903 [Abstract] [Full Text]  
• Kelso, A., Costelloe, E. O., Johnson, B. J., Groves, P., Buttigieg, K., Fitzpatrick, D. R. (2002). The genes for perforin, granzymes A-C and IFN-{gamma} are differentially expressed in single CD8+ T cells during primary activation. Int Immunol 14: 605-613 [Abstract] [Full Text]  
• White, G. P., Watt, P. M., Holt, B. J., Holt, P. G. (2002). Differential Patterns of Methylation of the IFN-{gamma} Promoter at CpG and Non-CpG Sites Underlie Differences in IFN-{gamma} Gene Expression Between Human Neonatal and Adult CD45RO- T Cells. J. Immunol. 168: 2820-2827 [Abstract] [Full Text]  
• Kienzle, N., Buttigieg, K., Groves, P., Kawula, T., Kelso, A. (2002). A Clonal Culture System Demonstrates That IL-4 Induces a Subpopulation of Noncytolytic T Cells with Low CD8, Perforin, and Granzyme Expression. J. Immunol. 168: 1672-1681 [Abstract] [Full Text]  
• Young, J., Biden, K. G., Simms, L. A., Huggard, P., Karamatic, R., Eyre, H. J., Sutherland, G. R., Herath, N., Barker, M., Anderson, G. J., Fitzpatrick, D. R., Ramm, G. A., Jass, J. R., Leggett, B. A. (2000). HPP1: A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proc. Natl. Acad. Sci. USA 10.1073/pnas.011415298v1 [Abstract] [Full Text]  
• Panus, J. F., McHeyzer-Williams, L. J., McHeyzer-Williams, M. G. (2000). Antigen-specific T Helper Cell Function: Differential Cytokine Expression in Primary and Memory Responses. J. Exp. Med. 192: 1301-1316 [Abstract] [Full Text]  
• Grunau, C., Hindermann, W., Rosenthal, A. (2000). Large-scale methylation analysis of human genomic DNA reveals tissue-specific differences between the methylation profiles of genes and pseudogenes. Hum Mol Genet 9: 2651-2663 [Abstract] [Full Text]  
• Jelley-Gibbs, D. M., Lepak, N. M., Yen, M., Swain, S. L. (2000). Two Distinct Stages in the Transition from Naive CD4 T Cells to Effectors, Early Antigen-Dependent and Late Cytokine-Driven Expansion and Differentiation. J. Immunol. 165: 5017-5026 [Abstract] [Full Text]  
• Tsunobuchi, H., Nishimura, H., Goshima, F., Daikoku, T., Nishiyama, Y., Yoshikai, Y. (2000). Memory-Type CD8+ T Cells Protect IL-2 Receptor {alpha}-Deficient Mice from Systemic Infection with Herpes Simplex Virus Type 2. J. Immunol. 165: 4552-4560 [Abstract] [Full Text]  
• Lanzavecchia, A., Sallusto, F. (2000). Dynamics of T Lymphocyte Responses: Intermediates, Effectors, and Memory Cells. Science 290: 92-97 [Abstract] [Full Text]  
• Cho, B. K., Rao, V. P., Ge, Q., Eisen, H. N., Chen, J. (2000). Homeostasis-stimulated Proliferation Drives Naive T Cells to Differentiate Directly into Memory T Cells. J. Exp. Med. 192: 549-556 [Abstract] [Full Text]  
• Goldrath, A. W., Bogatzki, L. Y., Bevan, M. J. (2000). Naive T Cells Transiently Acquire a Memory-like Phenotype during Homeostasis-driven Proliferation. J. Exp. Med. 192: 557-564 [Abstract] [Full Text]  
• Rogers, P. R., Dubey, C., Swain, S. L. (2000). Qualitative Changes Accompany Memory T Cell Generation: Faster, More Effective Responses at Lower Doses of Antigen. J. Immunol. 164: 2338-2346 [Abstract] [Full Text]  
• Karulin, A. Y., Hesse, M. D., Tary-Lehmann, M., Lehmann, P. V. (2000). Single-Cytokine-Producing CD4 Memory Cells Predominate in Type 1 and Type 2 Immunity. J. Immunol. 164: 1862-1872 [Abstract] [Full Text]  
• Nishimura, H., Yajima, T., Naiki, Y., Tsunobuchi, H., Umemura, M., Itano, K., Matsuguchi, T., Suzuki, M., Ohashi, P. S., Yoshikai, Y. (2000). Differential Roles of Interleukin 15 mRNA Isoforms Generated by Alternative Splicing in Immune Responses In Vivo. J. Exp. Med. 191: 157-170 [Abstract] [Full Text]  
• Hmadcha, A., Bedoya, F. J., Sobrino, F., Pintado, E. (1999). Methylation-dependent Gene Silencing Induced by Interleukin 1{beta} Via Nitric Oxide Production. J. Exp. Med. 190: 1595-1604 [Abstract] [Full Text]  
• Richter, A., Lohning, M., Radbruch, A. (1999). Instruction for Cytokine Expression in T Helper Lymphocytes in Relation to Proliferation and Cell Cycle Progression. J. Exp. Med. 190: 1439-1450 [Abstract] [Full Text]  
• Murali-Krishna, K., Lau, L. L., Sambhara, S., Lemonnier, F., Altman, J., Ahmed, R. (1999). Persistence of Memory CD8 T Cells in MHC Class I-Deficient Mice. Science 286: 1377-1381 [Abstract] [Full Text]  
• Doyle, A. G., Buttigieg, K., Groves, P., Johnson, B. J., Kelso, A. (1999). The Activated Type 1-polarized CD8+ T Cell Population Isolated from an Effector Site Contains Cells with Flexible Cytokine Profiles. J. Exp. Med. 190: 1081-1092 [Abstract] [Full Text]  
• Haynes, L., Linton, P.-J., Eaton, S. M., Tonkonogy, S. L., Swain, S. L. (1999). Interleukin 2, but Not Other Common {gamma} Chain–binding Cytokines, Can Reverse the Defect in Generation of CD4 Effector T Cells from Naive T Cells of Aged Mice. J. Exp. Med. 190: 1013-1024 [Abstract] [Full Text]  
• Dottori, M., Down, M., Huttmann, A., Fitzpatrick, D. R., Boyd, A. W. (1999). Cloning and Characterization of EphA3 (Hek) Gene Promoter: DNA Methylation Regulates Expression in Hematopoietic Tumor Cells. Blood 94: 2477-2486 [Abstract] [Full Text]  
• 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]  
• Fitzpatrick, D. R., Shirley, K. M., Kelso, A. (1999). Cutting Edge: Stable Epigenetic Inheritance of Regional IFN-{gamma} Promoter Demethylation in CD44highCD8+ T Lymphocytes. J. Immunol. 162: 5053-5057 [Abstract] [Full Text]  
• Kelso, A., Groves, P., Ramm, L., Doyle, A. G. (1999). Single-cell analysis by RT-PCR reveals differential expression of multiple type 1 and 2 cytokine genes among cells within polarized CD4+ T cell populations. Int Immunol 11: 617-621 [Abstract] [Full Text]  
• Young, J., Biden, K. G., Simms, L. A., Huggard, P., Karamatic, R., Eyre, H. J., Sutherland, G. R., Herath, N., Barker, M., Anderson, G. J., Fitzpatrick, D. R., Ramm, G. A., Jass, J. R., Leggett, B. A. (2001). HPP1: A transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. Proc. Natl. Acad. Sci. USA 98: 265-270 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS