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Temporal and Subunit-specific Modulations of the Rel/NF-κB Transcription Factors Through CD28 Costimulation*

Stimulation of highly purified primary T lymphocytes through CD2 and CD28 adhesion molecules induces a long-term proliferation, dependent on persistent autocrine secretion of interleukin 2 (IL-2), high and prolonged expression of inducible CD25/IL-2 receptor α chain (IL-2Rα), and secretion of growth factors such as the granulocyte-macrophage colony-stimulating factor (GM-CSF). CD28 costimulation appears to activate cytokine gene expression through conserved κB-related CD28 response (CD28RE) or cytokine 1 (CK-1) elements in addition to canonical NF-κB-binding sites. In this report, we assess: 1) the evolution of the expression, over an 8-day time period, of the Rel/NF-κB family of proteins in costimulated versus TcR/CD3-stimulated primary T cells; 2) the impact of changes on the in vitro occupancy of GM-CSF κB and CK-1, as well as IL-2Rα κB sites; and 3) the differential regulation of newly synthesized p65 and c-Rel by IκB proteins. We show that CD2+CD28 stimulation specifically induces, at maximal T cell proliferation phase, sustained nuclear overexpression ofNFKB2 p52 and c-Rel subunits which might rely on long-lasting processing of p100 precursor for p52 and increased neosynthesis of c-Rel. This up-regulation correlates with sustained occupancy of GM-CSF κB and CK-1 elements by both proteins. Conversely, these subunits do not appear to bind to the IL-2Rα κB site. Costimulation, but not TcR/CD3 stimulation, appears supported by sustained down-regulation of both IκBα and -β regulators. Furthermore, contrary to p65, c-Rel appears to display little affinity for p105, p100 and IκBα regulators.