TY - JOUR
T1 - Aging-related deficiency of CD28 expression in CD4+ T cells is associated with the loss of gene-specific nuclear factor binding activity
AU - Vallejo, Abbe N.
AU - Nestel, Achim R.
AU - Schirmer, Michael
AU - Weyand, Cornelia M.
AU - Goronzy, Jörg J.
PY - 1998/4/3
Y1 - 1998/4/3
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.273.14.8119
DO - 10.1074/jbc.273.14.8119
M3 - Article
C2 - 9525915
AN - SCOPUS:0032478816
SN - 0021-9258
VL - 273
SP - 8119
EP - 8129
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -