CD28 loss in senescent CD4⁺ T cells: Reversal by interleukin-12 stimulation

CD28 is the quintessential costimulatory molecule expressed on CD4⁺ and CD8⁺ T cells. During chronic infections and the normal aging process, CD28 expression is lost, compromising the functional activity of T cells. CD28 loss is promoted by replicative stress, particularly in the presence of tumor necrosis factor-α, owing to an inoperative CD28 initiator element. It is currently unknown whether CD28 loss is irreversible. The present study examined cytokines for their ability to reinduce CD28 expression. CD4⁺CD28^null T cells constitutively expressed interleukin-12 (IL-12) α and β receptors, which were functional and allowed for the up-regulation of the signal transducer and activator of transcription-4 (STAT-4)-dependent gene CD161. Costimulation of the T-cell and IL-12 receptors induced the transcription of CD28 in approximately 50% of CD4⁺CD28^null T-cell clones and lines. IL-12 by itself did not restore CD28 expression. Up-regulation of CD28 after IL-12 exposure correlated with the reassembly of the CD28-initiator protein complex. The re-expressed CD28 was functional and restored the ability of CD4⁺CD28^null T cells to express CD25 and CD40 ligand. Our data suggest that IL-12 may, in part, functionally rescue senescent CD4⁺ T cells.