Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells
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In T cells anergy may be evoked by an unbalanced stimulation of the T-cell receptor in the absence of costimulation. Anergic T cells are unresponsive to new antigen receptor engagement and do not produce interleukin 2. We present evidence that anergizing stimuli induce changes in histone acetylation, which mediates transcriptional repression of interleukin 2 expression. In response to calcium signaling, anergic T cells up-regulate the expression of Ikaros, a zinc finger transcription factor essential for lymphoid lineage determination. Ikaros binds to the interleukin 2 promoter where it induces histone deacetylation. Confirming the role of Ikaros in the induction of T-cell anergy, cells with reduced Ikaros activity show defective inactivation in response to an anergizing stimulus. We propose a model in which tolerizing stimuli induce epigenetic changes on the interleukin 2 locus that are responsible for the stable inhibition of the expression of this cytokine in anergic T cells.
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Epigenetic factors including IKAROS (via acetylation) and Sirt1 participate in histone modifications that promote T cell anergy.
“Epigenetic factors such as IKAROS (through acetylation) [25] and Sirt1 are involved in histone modifications that promote T cell anergy [26,27].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [27]
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Cites
Transcriptional regulation by calcium, calcineurin, and NFAT
Hogan, P. G., Chen, L., Nardone, J., & Rao, A. (2003) · Genes & Development · doi:10.1101/gad.1102703 · Cited by 1,991 · see citing works
NFAT proteins: key regulators of T-cell development and function
Macián, F. (2005) · Nature reviews. Immunology · doi:10.1038/nri1632 · Cited by 1,575 · see citing works
Schwartz, R. H. (2003) · Annual Review of Immunology · doi:10.1146/annurev.immunol.21.120601.141110 · Cited by 1,487 · see citing works
Association of transcriptionally silent genes with Ikaros complexes at centromeric heterochromatin.
Brown, K., Guest, S. S., Smale, S., Hahm, K., Merkenschlager, M., & Fisher, A. (1997) · Cell · doi:10.1016/s0092-8674(00)80472-9 · Cited by 824 · see citing works
Partners in transcription: NFAT and AP-1
Macián, F., López‐Rodríguez, C., & Rao, A. (2001) · Oncogene · doi:10.1038/sj.onc.1204386 · Cited by 766 · see citing works
Induction of Peripheral T Cell Tolerance In Vivo Requires CTLA-4 Engagement
Perez, V. L., Parijs, L. V., Biuckians, A., Zheng, X. X., Strom, T. B., & Abbas, A. K. (1997) · Immunity · doi:10.1016/s1074-7613(00)80284-8 · Cited by 715 · see citing works
Transcriptional Mechanisms Underlying Lymphocyte Tolerance
Macián, F., Garcia-Cozar, F. J., Im, S., Horton, H. F., Byrne, M. C., & Rao, A. (2002) · Cell · doi:10.1016/s0092-8674(02)00767-5 · Cited by 687 · see citing works
Modulation of Chromatin Structure Regulates Cytokine Gene Expression during T Cell Differentiation
Agarwal, S., & Rao, A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80642-1 · Cited by 687 · see citing works
Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.
Friedman, A., & Weiner, H. L. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.14.6688 · Cited by 638 · see citing works
Wang, J., Nichogiannopoulou, A., Wu, L. J., Sun, L., Sharpe, A. H., Bigby, M. E., & Georgopoulos, K. (1996) · Immunity · doi:10.1016/s1074-7613(00)80269-1 · Cited by 614 · see citing works
Ikaros DNA-Binding Proteins Direct Formation of Chromatin Remodeling Complexes in Lymphocytes
Kim, J., Sif, S., Jones, B., Jackson, A., Koipally, J., Heller, E., Winandy, S., Viel, A., Sawyer, A., Ikeda, T., et al. (1999) · Immunity · doi:10.1016/s1074-7613(00)80034-5 · Cited by 587 · see citing works
Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation.
Gimmi, C. D., Freeman, G. J., Gribben, J. G., Gray, G. S., & Nadler, L. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.14.6586 · Cited by 548 · see citing works
TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes
Avni, O., Lee, D. H., Macián, F., Szabo, S. J., Glimcher, L. H., & Rao, A. (2002) · Nature Immunology · doi:10.1038/ni808 · Cited by 521 · see citing works
Calcineurin imposes T cell unresponsiveness through targeted proteolysis of signaling proteins
Heissmeyer, V., Macián, F., Im, S., Varma, R., Feske, S., Venuprasad, K., Gu, H., Liu, Y., Dustin, M. L., & Rao, A. (2004) · Nature Immunology · doi:10.1038/ni1047 · Cited by 515 · see citing works
Bruniquel, D., & Schwartz, R. H. (2003) · Nature Immunology · doi:10.1038/ni887 · Cited by 457 · see citing works
CTLA-4 regulates induction of anergy in vivo
Greenwald, R. J., Boussiotis, V. A., Lorsbach, R. B., Abbas, A. K., & Sharpe, A. H. (2001) · Immunity · doi:10.1016/s1074-7613(01)00097-8 · Cited by 428 · see citing works
Blocked Signal Transduction to the ERK and JNK Protein Kinases in Anergic CD4 + T Cells
Li, W., Whaley, C. D., Mondino, A., & Mueller, D. L. (1996) · Science · doi:10.1126/science.271.5253.1272 · Cited by 427 · see citing works
The Ikaros Gene Encodes a Family of Functionally Diverse Zinc Finger DNA-Binding Proteins
Molnár, A., & Georgopoulos, K. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.12.8292 · Cited by 425 · see citing works
Maintenance of Human T Cell Anergy: Blocking of IL-2 Gene Transcription by Activated Rap1
Boussiotis, V. A., Freeman, G. J., Berezovskaya, A., Barber, D. L., & Nadler, L. M. (1997) · Science · doi:10.1126/science.278.5335.124 · Cited by 408 · see citing works
Quill, H., & Schwartz, R. H. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.138.11.3704 · Cited by 388 · see citing works
Blocked Ras Activation in Anergic CD4 + T Cells
Fields, P. E., Gajewski, T. F., & Fitch, F. W. (1996) · Science · doi:10.1126/science.271.5253.1276 · Cited by 370 · see citing works
Jenkins, M. K., Chen, C., Jung, G., Mueller, D. L., & Schwartz, R. H. (1990) · The Journal of Immunology · doi:10.4049/jimmunol.144.1.16 · Cited by 355 · see citing works
Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction
Jeon, M.-S., Atfield, A., Venuprasad, K., Krawczyk, C., Sarao, R., Elly, C., Yang, C., Arya, S., Bachmaier, K., Su, L., et al. (2004) · Immunity · doi:10.1016/j.immuni.2004.07.013 · Cited by 348 · see citing works
Reversal of in vitro T cell clonal anergy by IL-2 stimulation
Beverly, B., Kang, S., Lenardo, M. J., & Schwartz, R. H. (1992) · International Immunology · doi:10.1093/intimm/4.6.661 · Cited by 333 · see citing works
Haematopoietic cell-fate decisions, chromatin regulation and ikaros
Georgopoulos, K. (2002) · Nature reviews. Immunology · doi:10.1038/nri747 · Cited by 324 · see citing works
Aiolos Regulates B Cell Activation and Maturation to Effector State
Wang, J.-H., Avitahl, N., Cariappa, A., Friedrich, C., Ikeda, T., Renold, A., Andrikopoulos, K., Liang, L., Pillai, S., Morgan, B. A., et al. (1998) · Immunity · doi:10.1016/s1074-7613(00)80637-8 · Cited by 321 · see citing works
Repression by Ikaros and Aiolos is mediated through histone deacetylase complexes
Koipally, J., Renold, A., Kim, J., & Georgopoulos, K. (1999) · The EMBO Journal · doi:10.1093/emboj/18.11.3090 · Cited by 304 · see citing works
Disruption of diacylglycerol metabolism impairs the induction of T cell anergy
Olenchock, B. A., Guo, R., Carpenter, J. H., Jordan, M. S., Topham, M. K., Koretzky, G. A., & Zhong, X.-P. (2006) · Nature Immunology · doi:10.1038/ni1400 · Cited by 302 · see citing works
Anandasabapathy (2003) · doi:10.1016/s1074-7613(03)00084-0 · Cited by 285 · see citing works
Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells
Tzachanis, D., Freeman, G. J., Hirano, N., van Puijenbroek, A. A. F. L., Delfs, M. W., Berezovskaya, A., Nadler, L. M., & Boussiotis, V. A. (2001) · Nature Immunology · doi:10.1038/ni730 · Cited by 273 · see citing works
T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α
Zha, Y., Marks, R., Ho, A. W., Peterson, A., Janardhan, S. V., Brown, I. E., Praveen, K., Stang, S. L., Stone, J. C., & Gajewski, T. F. (2006) · Nature Immunology · doi:10.1038/ni1394 · Cited by 267 · see citing works
The Dynamics of Chromatin Remodeling at Promoters
Mellor, J. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.06.023 · Cited by 221 · see citing works
Koipally, J., & Georgopoulos, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000254200 · Cited by 193 · see citing works
Chromatin Structure and Gene Regulation in the Immune System
Smale, S. T., & Fisher, A. G. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.100301.064739 · Cited by 176 · see citing works
Ikaros Sets Thresholds for T Cell Activation and Regulates Chromosome Propagation
Avitahl, N., Winandy, S., Friedrich, C., Jones, B., Ge, Y., & Georgopoulos, K. (1999) · Immunity · doi:10.1016/s1074-7613(00)80033-3 · Cited by 173 · see citing works
Macián, F., Im, S., Garcia-Cozar, F. J., & Rao, A. (2004) · Current Opinion in Immunology · doi:10.1016/j.coi.2004.01.013 · Cited by 159 · see citing works
Trinh, L. A., Ferrini, R., Cobb, B. S., Weinmann, A. S., Hahm, K., Ernst, P., Garraway, I. P., Merkenschlager, M., & Smale, S. T. (2001) · Genes & Development · doi:10.1101/gad.905601 · Cited by 154 · see citing works
The −180 Site of the IL-2 Promoter Is the Target of CREB/CREM Binding in T Cell Anergy
Powell, J. D., Lerner, C. G., Ewoldt, G. R., & Schwartz, R. H. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.12.6631 · Cited by 124 · see citing works
Signals from CD28 Induce Stable Epigenetic Modification of the IL-2 Promoter
Thomas, R. M., Gao, L., & Wells, A. D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.8.4639 · Cited by 122 · see citing works
c-Rel Is Required for Chromatin Remodeling Across the IL-2 Gene Promoter
Rao, S., Gerondakis, S., Woltring, D., & Shannon, M. F. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3724 · Cited by 115 · see citing works
Seroogy, C. M., Soares, L. R. B., Ranheim, E. A., Su, L., Holness, C. L. L., Bloom, D. D., & Fathman, C. G. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.1.79 · Cited by 96 · see citing works
Li, L., Iwamoto, Y., Berezovskaya, A., & Boussiotis, V. A. (2006) · Nature Immunology · doi:10.1038/ni1398 · Cited by 90 · see citing works
Ward, S. B., Hernández‐Hoyos, G., Chen, F., Waterman, M. L., Reeves, R., & Rothenberg, E. V. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.12.2923 · Cited by 81 · see citing works
Su, L., Creusot, R. J., Gallo, E. M., Chan, S. M., Utz, P. J., Fathman, C. G., & Ermann, J. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.173.8.4994 · Cited by 76 · see citing works
Sun, J. L., Matthias, G., Mihatsch, M. J., Georgopoulos, K., & Matthias, P. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.4.1699 · Cited by 64 · see citing works
A Molecular Dissection of the Repression Circuitry of Ikaros
Koipally, J., & Georgopoulos, K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201694200 · Cited by 60 · see citing works
The control of T cell activation vs. tolerance
Abbas, A. K. (2003) · Autoimmunity Reviews · doi:10.1016/s1568-9972(03)00028-4 · Cited by 59 · see citing works
Evidence for Repression of IL-2 Gene Activation in Anergic T Cells
Telander, D. G., Malvey, E.-N., & Mueller, D. L. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1460 · Cited by 53 · see citing works
Assembly of silent chromatin during thymocyte development
Su, R., Sridharan, R., & Smale, S. T. (2005) · Seminars in Immunology · doi:10.1016/j.smim.2005.01.003 · Cited by 26 · see citing works
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Self-citation
- Authors
- Bandyopadhyay, S., Duré, M., Paroder, M., Soto-Nieves, N., Puga, I., & Macián, F.
- Affiliations
- Albert Einstein College of Medicine (US)
- Albert Einstein College of Medicine, Department of Pathology, Bronx, NY
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2006-12-05
- Volume
- 109
- Issue
- 7
- Pages
- 2878-2886
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1852212
- OpenAlex
- W2053841483
- Cited by
- 104
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 11 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 5 · 2013: 9 · 2012: 9
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM007288, GM007491, T32GM007491, T32GM007288)
- National Institute of Allergy and Infectious Diseases (R56AI059738, AI059738, R01AI059738)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- interleukin-2, Ikaros, histone acetylation, histone deacetylation, T cell anergy, transcriptional repression, interleukin-2 promoter, calcium signaling, epigenetic regulation, zinc finger transcription factor, T cell tolerance, costimulation
- MeSH terms
- Acetylation, Animals, Histones, Humans, Interleukin-2, Lymphocyte Activation, Mice, Inbred C57BL, Promoter Regions, Genetic, T-Lymphocytes, Transcription, Genetic, Clonal Anergy, Th1 Cells, Models, Immunological, Jurkat Cells, Epigenesis, Genetic, Mice, Ikaros Transcription Factor, In Vitro Techniques
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