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 survival is largely dictated by the provision of additional signals, such as those from costimulatory receptors and cytokine receptors. Whilst CD28-mediated signalling is increasingly associated with survival, ligation of alternative T-cell antigens, such as Fas (CD95), can trigger apoptosis. The T-cell response following antigen engagement may therefore be influenced by the relative expression levels of these coreceptors as well as by the availability of their ligands (CD80/86 and Fas-L). In this study we demonstrate functional interplay between the death receptor Fas and the costimulatory receptor CD28 in human T cells. In Jurkat T cells, we show that Fas signalling leads to rapid and selective CD28 down-regulation, and that this is associated with a specific decrease in mRNA for CD28, indicating that mechanisms exist which target CD28 at a transcriptional level. Moreover, cells that down-regulate CD28 also undergo apoptosis. Studies on activated human peripheral blood T cells demonstrate that cells expressing high levels of CD28 are resistant to Fas-mediated apoptosis whereas cells expressing low levels are more susceptible, implicating CD28 in the provision of anti-apoptotic signals. Consistent with this hypothesis, direct ligation of CD28 using B7 transfectants concomitant with anti-Fas challenge protects from apoptosis. Since antigen-presenting cells may express Fas-L under certain circumstances, the maintenance of T-cell CD28 expression may be crucial for the prevention of Fas-mediated apoptosis during the course of antigen engagement.
Bath Institute for Rheumatic Diseases, UK.
L S
LS
Walker
J D
JD
McLeod
G
G
Boulougouris
Y I
YI
Patel
N D
ND
Hall
D M
DM
Sansom
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology*; D018929:Cell Culture Techniques; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology*
D018106:CD28 Antigens; D012333:RNA, Messenger; D019014:fas Receptor; D005047:Etoposide; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate