DOWN-REGULATION OF CD28 VIA FAS (CD95) - INFLUENCE OF CD28 ON T-CELL APOPTOSIS

Following antigen engagement of the T-cell receptor (TCR), T-cell surv ival is largely dictated by the provision of additional signals, such as those from costimulatory receptors and cytokine receptors. Whilst C D28-mediated signalling is increasingly associated with survival, liga tion of alternative T-cell antigens, such as Fas (CD95), can trigger a poptosis. The T-cell response following antigen engagement may therefo re be influenced by the relative expression levels of these coreceptor s as well as by the availability of their ligands (CD80/86 and Fas-L). In this study we demonstrate functional interplay between the death r eceptor Fas and the costimulatory receptor CD28 in human T cells. In J urkat T cells, we show that Fas signalling leads to rapid and selectiv e CD28 down-regulation, and that this is associated with a specific de crease in mRNA for CD28, indicating that mechanisms exist which target CD28 at a transcriptional level. Moreover, cells that down-regulate C D28 also undergo apoptosis. Studies on activated human peripheral bloo d T cells demonstrate that cells expressing high levels of CD28 are re sistant to Fas-mediated apoptosis whereas cells expressing low levels are more susceptible, implicating CD28 in the provision of anti-apopto tic signals. Consistent with this hypothesis, direct ligation of CD28 using B7 transfectants concomitant with anti-Fas challenge protects fr om apoptosis. Since antigen-presenting cells may express Fas-L under c ertain circumstances, the maintenance of T-cell CD28 expression may be crucial for the prevention of Fas-mediated apoptosis during the cours e of antigen engagement.