Down-Regulation of CD28 Expression by TNF-α
Open accessAbstract
Aging and chronic inflammatory syndromes, such as rheumatoid arthritis, are associated with high frequencies of CD4+CD28null T cells, which are rarely seen in healthy individuals younger than 40 years. Inasmuch as rheumatoid arthritis and aging are also associated with elevated levels of TNF-α, we examined whether this proinflammatory cytokine influences CD28 expression. Incubation of T cell lines and clones as well as Jurkat cells with TNF-α induced a reduction in the levels of cell surface expression of CD28. This effect of TNF-α was reversible; however, continuous culture of CD4+CD28+ T cell clones in TNF-α resulted in the appearance of a CD28null subset. In reporter gene bioassays, TNF-α was found to inhibit the activity of the CD28 minimal promoter. Inactivation of the promoter was accompanied by a marked reduction in DNA-protein complex formation by two DNA sequence motifs corresponding to the transcriptional initiator of the CD28 gene. Indeed, in vitro transcription assays showed that nuclear extracts from TNF-α-treated cells failed to activate transcription of DNA templates under the control of a consensus TATA box and the CD28 initiator sequences. In contrast, similar extracts from unstimulated T cells supported transcription. These results demonstrate that TNF-α directly influences CD28 gene transcription. We propose that the emergence of CD4+CD28null T cells in vivo is facilitated by increased production of TNF-α.
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Self-citation
- Authors
- Bryl, E., Vallejo, A. N., Weyand, C. M., & Goronzy, J. J.
- Affiliations
- Mayo Clinic (US)
- Departments of Medicine and Immunology, Mayo Clinic , Rochester, MN 55905
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2001-09
- Volume
- 167
- Issue
- 6
- Pages
- 3231-3238
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1764386432
- Cited by
- 264
- References
- 60
- Citations by year
- 2026: 5 · 2024: 9 · 2023: 5 · 2022: 9 · 2021: 9 · 2020: 14 · 2019: 13 · 2018: 8 · 2017: 11 · 2016: 9 · 2015: 16 · 2014: 11 · 2013: 12 · 2012: 12
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Foundation for Medical Education and Research (R01 AR41974)
- National Institutes of Health
- National Institute on Aging (R01AG015043, R01AG15043)
- Fogarty International Center
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR041974, R01 AR 41974, R03-AR45830, R03AR045830)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- CD28, TNF-α, CD4+ T cells, rheumatoid arthritis, aging, transcriptional regulation, TATA box, protein-DNA complex, chronic inflammation, T cell activation
- MeSH terms
- Aging, Arthritis, Rheumatoid, Camptothecin, Cell Line, Cell-Free System, Clone Cells, Humans, Lymphocyte Activation, Neoplasm Proteins, Promoter Regions, Genetic, RNA, Messenger, RNA, Neoplasm, T-Lymphocytes, Transcription, Genetic, Tumor Necrosis Factor-alpha, CD4-Positive T-Lymphocytes, Down-Regulation, TATA Box, Apoptosis, Annexin A5, Genes, Reporter, CD28 Antigens, Jurkat Cells
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