Adaptation of human CD4+ T cells to pathophysiological hypoxia: a transcriptome analysis

J Rheumatol. 2009 Dec;36(12):2655-69. doi: 10.3899/jrheum.090255. Epub 2009 Nov 2.


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-1alpha (HIF-1alpha) 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-1alpha 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / physiopathology
  • CD4-Positive T-Lymphocytes* / chemistry
  • CD4-Positive T-Lymphocytes* / immunology
  • Cell Hypoxia* / immunology
  • Cells, Cultured
  • Gene Expression Profiling*
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Microarray Analysis
  • Oxygen / metabolism
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology
  • Synovial Membrane / pathology


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Oxygen