Down-regulation of CD28 expression by TNF-α

E. Bryl, A. N. Vallejo, C. M. Weyand, J. J. Goronzy

Research output: Contribution to journalArticlepeer-review

209 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3231-3238
Number of pages8
JournalJournal of Immunology
Issue number6
StatePublished - Sep 15 2001

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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