Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity

Abbe N. Vallejo, Achim R. Nestel, Michael Schirmer, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

141 Scopus citations

Abstract

Changes in T cell populations and concomitant perturbation of T cell effector functions have been postulated to account for many aging-related immune dysfunctions. Here, we report that high frequencies of CD28(null) CD4+ T cells were found in elderly individuals. Because deviations in the function of these unusual CD4+ T cells might be directly related to CD28 deficiency, we examined the molecular basis for the loss of CD28 expression in CD4+ T cells. In reporter gene bio-assays, the minimal promoter of the CD28 gene was mapped to the proximal 400 base pairs (bp) of the 5' untranslated region. CD28 deficiency was associated with the loss of two noncompeting binding activities within a 67-bp segment of the minimal promoter. These binding activities were not competed by consensus Ets, Elk, or AP3 motifs that were found within the sequence stretch. The DNA-protein complexes were also not recognized by antibodies to Ets-related transcription factors. Furthermore, introduction of mutations into the 67-bp segment at positions corresponding to the two DNA-protein interaction sites, e.i. nucleotides spanning -206 to - 179 and -171 to -148, resulted in the loss of specific nuclear factor biding activities and the abrogation of promoter activity. These observations implicate at least two regulatory motifs in the constitutive expression of CD28. The loss of binding activity of transacting factors specific for these sequences may contribute to the accumulation CD4+CD28(null) T cells during aging.

Original languageEnglish (US)
Pages (from-to)8119-8129
Number of pages11
JournalJournal of Biological Chemistry
Volume273
Issue number14
DOIs
StatePublished - Apr 3 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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