CD28 COSTIMULATION UP-REGULATES LONG-TERM IL-2R-BETA EXPRESSION IN HUMAN T-CELLS THROUGH COMBINED TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL REGULATION

Costimulatory molecules such as CD28 are required for induction of T c ell clonal expansion and for prevention of T cell un responsiveness. I n combination with either CD3 or CD2 triggering, CD28 was shown to enh ance T cell proliferation, cytolytic activity, production of cytokines and especially of IL-2, and expression of the IL-2R alpha-chain (IL-2 R alpha). We and others have demonstrated that the costimulatory effec t of CD28 on both IL-2 and IL-2R alpha expression results from a coord inated transcriptional activation of their genes and transcript stabil ization. We show here that the CD28 stimulation, together with CD2, le ads to a prolonged up-regulation of the constitutive expression of the IL-2R beta-chain in human peripheral T cells. As for IL-2R alpha, the increase in IL-2R beta gene expression seems to result from both tran scriptional activation and transcript stabilization. In addition, IL-2 differentially regulates its own receptors, as only expression of IL- 2R alpha, but not of IL-2R beta, is largely inhibited, at both the mRN A and protein levels, by blocking IL-2R mAbs. We propose that the long lasting T cell proliferation mediated by the CD2 and CD28 costimulati on is mainly the consequence of the high and prolonged expression of b oth the IL-2R alpha- and beta-chains.