NFATc1 Regulates PD-1 Expression upon T Cell Activation
Open accessAbstract
PD-1 is a transmembrane protein involved in the regulation of immunological tolerance. Multiple studies have reported an association between high levels of PD-1 expressed on T cell surfaces and exhaustion in lymphocyte populations when challenged by chronic viral infections, such as HIV. By using model systems consisting of murine EL4 cells, which constitutively express PD-1, and primary murine CD8 T cells that express PD-1 upon T cell stimulation, we have identified two tissue-specific hypersensitive sites at the 5′ CR of the PD-1 locus. Gene reporter assays in CD8 T cells have shown that one of these sites has robust transcriptional activity in response to cell stimulation. Cell treatment with the calcineurin inhibitor cyclosporine A or a NFAT-specific inhibitor led to a sharp reduction in PD-1 expression in the constitutive and inducible systems. Furthermore, analysis of this region by chromatin immunoprecipitation assay revealed NFATc1 binding associated with gene activation in EL4 and primary CD8 T cells. Mutation of the NFATc1 binding site in PD-1 reporter constructs resulted in a complete loss of promoter activity. Together, these results demonstrate that PD-1 gene regulation occurs in part via the recruitment of NFATc1 to a novel regulatory element at the pdcd1 locus and provides the molecular mechanism responsible for the induction of PD-1 in response to T cell stimulation.
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Exhausted cells presented high activity of Nfatc1 regulon, presumably involved in regulating the exhaustion process.
“Exhausted cells presented a high activity of Nfatc1 regulon, which is presumably involved in regulating the exhaustion process (50–53).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [52]
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- Authors
- Oestreich, K. J., Yoon, H., Ahmed, R., & Boss, J. M.
- Affiliations
- Department of Microbiology and Immunology
- Emory University (US)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-10-01
- Volume
- 181
- Issue
- 7
- Pages
- 4832-4839
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC2645436
- OpenAlex
- W1566018542
- Cited by
- 416
- References
- 56
- Citations by year
- 2026: 25 · 2025: 26 · 2024: 38 · 2023: 26 · 2022: 31 · 2021: 37 · 2020: 27 · 2019: 35 · 2018: 28 · 2017: 33 · 2016: 27 · 2015: 20 · 2014: 21 · 2013: 13 · 2012: 9
- FWCI
- 2.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM047310)
- National Institute of Allergy and Infectious Diseases (P01AI080192, T32AI007610)
- 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
- PD-1, NFATc1, T cell activation, CD8+ T cells, transcriptional regulation, calcineurin, cyclosporine, T cell exhaustion, HIV, EL4 cells
- MeSH terms
- Animals, Antigens, Surface, Cells, Cultured, Deoxyribonuclease I, Gene Expression Regulation, Genetic Markers, Lymphocyte Activation, Mice, Inbred C57BL, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Conserved Sequence, CD8-Positive T-Lymphocytes, Protein Transport, Cell Line, Tumor, NFATC Transcription Factors, Apoptosis Regulatory Proteins, Mice, Programmed Cell Death 1 Receptor
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