Modulation of CD28 expression: Distinct regulatory pathways during activation and replicative senescence

The costimulatory molecule CD28 has a restricted tissue distribution and is expressed on T cells and some plasmacytoma cells. Although CD28 is constitutively expressed, its expression is transiently down-regulated following T cell activation and declines progressively with in vitro senescence. In vivo, CD8⁺ T cells and, less frequently, CD4⁺ T cells may completely lose CD28 surface expression during chronic infections and with aging. This correlates with changes of nuclear protein-binding activities to two motifs, site α and β, within the CD28 minimal promoter. Both α- and β-bound complexes are found only in lymphoid tissues, in CD28⁺ T cells, and in some transformed B cells. These complexes are coordinately expressed except during replicative senescence, which is characterized by the down- modulation of site β- but not site α-binding activities. In contrast, T cell activation induces a parallel decline in both site α- and β-binding activities. CD4⁺ and CD8⁺ T cells differ in their β-binding profiles, which may explain the more pronounced down-regulation of CD28 in senescent CD8⁺ T cells. In vivo expanded CD4⁺CD28(null) and CD8⁺CD28(null) T cells uniformly lack α- and β-bound complexes, resembling the pattern seen in chronically activated cells and not of senescent cells.