Transcriptional complexes formed by NFAT dimers regulate the induction of T cell tolerance
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In T cells, anergy can be induced after T cell receptor engagement in the absence of costimulation. Under these conditions, the expression of a specific set of anergy-associated genes is activated. Several lines of evidence suggest that nuclear factor of activated T cells (NFAT) proteins may regulate the expression of many of those genes; however, the nature of the complexes responsible for the induction of this new program of gene expression is unknown. Here, we show that transcriptional complexes formed by NFAT homodimers are directly responsible for the activation of at least two anergy-inducing genes, Grail and Caspase3. Our data shows that Grail expression is activated by direct binding of NFAT dimers to the Grail promoter at two different sites. Consequently, a mutant NFAT protein with impaired ability to dimerize is not able to induce an unresponsive state in T cells. Our results not only identify a new biological function for NFAT dimers but also reveal the different nature of NFAT-containing complexes that induce anergy versus those that are activated during a productive immune response. These data also establish a basis for the design of immunomodulatory strategies that specifically target each type of complex.
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The genetic reprogramming effects of the Ca2+ imbalance are hypothesized to be mediated by NFAT homodimer formation and transcription of anergy-inducing genes.
“The effects of this imbalance on the genetic reprogramming of these cells have been hypothesized to be mediated by NFAT homodimer formation and transcription of anergy-inducing genes [21,22].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [22]
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“…(Figure 4C) and no enrichment for kB-like sites such as the site in the Rnf128 promoter that binds NFAT1 homodimers (50- GTAACGTTTCC-30 or 50-GGATTCTTCC-30) (Soto-Nieves et al., 2009); Rnf128, which encodes the E3 ligase Grail, is upregulated in anergic CD4+ T cells (Fathman and Lineberry, 2007).”
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- Authors
- Soto-Nieves, N., Puga, I., Abe, B. T., Bandyopadhyay, S., Baine, I., Rao, A., & Macian, F.
- Affiliations
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461 1
- Albert Einstein College of Medicine (US)
- Harvard University (US)
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2009-03-23
- Volume
- 206
- Issue
- 4
- Pages
- 867-876
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2715123
- OpenAlex
- W2127082390
- Cited by
- 86
- References
- 58
- Citations by year
- 2026: 3 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 8 · 2020: 9 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 12
- FWCI
- 3.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- University of Southern California
- National Institutes of Health
- National Cancer Institute (CA-42471, R01CA042471, R37CA042471)
- National Institute of General Medical Sciences (GM007288, T32GM007288)
- National Institute of Allergy and Infectious Diseases (R56AI059738, AI059738, AI48213, R01AI048213, R01AI059738)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- 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
- Keywords
- NFAT, T cell anergy, T cell tolerance, transcriptional complex, GRAIL, caspase-3, T cell receptor signaling, costimulation, transcriptional activation, immunomodulation
- MeSH terms
- Gene Expression Regulation, Humans, Immune Tolerance, Mutation, Promoter Regions, Genetic, Receptors, Antigen, T-Cell, T-Lymphocytes, Transcription, Genetic, Jurkat Cells, Dimerization, Ubiquitin-Protein Ligases, NFATC Transcription Factors, Caspase 3
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