Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis
Open accessAbstract
Objective.: Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO 2< 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells. Methods.: We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1α (HIF-1α) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection. Results.: In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1α is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism. Conclusion.: Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.
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T cells present in inflammatory lesions in inflammatory bowel disease and rheumatoid arthritis express Hif-1α.
“T cells present in inflammatory lesions in inflammatory bowel disease (Crohn’s disease and ulcerative colitis) [34] and rheumatoid arthritis [35] express Hif-1α.”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [35]
Hypoxic exposure of T cells results in modest Hif-1α stabilization.
“hypoxic exposure of T cells results in modest Hif-1α stabilization [35]”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [35]
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- Authors
- GABER, T., HÄUPL, T., SANDIG, G., TYKWINSKA, K., FANGRADT, M., TSCHIRSCHMANN, M., HAHNE, M., DZIURLA, R., EREKUL, K., LAUTENBACH, M., KOLAR, P., BURMESTER, G.-R., & BUTTGEREIT, F.
- Affiliations
- German Rheumatism Research Centre (DE)
- Venue
- The Journal of Rheumatology
- Publisher
- The Journal of Rheumatology
- Published
- 2009-11-02
- Volume
- 36
- Issue
- 12
- Pages
- 2655-2669
- ISSN
- 0315-162X (ISSN-L)
- 1499-2752
- OpenAlex
- W1973770560
- Cited by
- 47
- References
- 51
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 5 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 3 · 2012: 9
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Rheumatology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung (01GS0413, 01GS0160, 01GS0110)
- Topics
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- hypoxia, CD4+ T cells, rheumatoid arthritis, synovium, hypoxia-inducible factor-1α, transcriptome, gene expression, joint inflammation, T cell metabolism, T cell proliferation
- MeSH terms
- Animals, Arthritis, Rheumatoid, Cells, Cultured, Gene Expression Regulation, Humans, Oxygen, Synovial Membrane, CD4-Positive T-Lymphocytes, Cell Hypoxia, Gene Expression Profiling, Microarray Analysis, Hypoxia-Inducible Factor 1, alpha Subunit
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