Synergistic induction of CTLA-4 expression by costimulation with TCR plus CD28 signals mediated by increased transcription and messenger ribonucleic acid stability.
T cell activation requires at least two signals transduced by the Ag-specific TCR plus a costimulatory receptor. The CD28 costimulatory molecule has been shown to promote T cell proliferation and cytokine production. CTLA-4, a cell surface molecule homologous to CD28, can function as a repressor of T cell activation. Thus, CTLA-4 and CD28 may have opposing functions during T cell activation. CTLA-4 is expressed at low levels on resting T cells and up-regulated after T cell activation. Regulation of CTLA-4 expression is critical to the normal regulation of immunity. For example, CTLA-4-deficient mice develop early onset lethal autoimmunity. We previously showed that CTLA-4 transcription is increased after T cell activation and that induction was controlled by 335 bp of CTLA-4 upstream sequence. In this work, we show that cell surface CTLA-4 expression is increased synergistically by TCR plus CD28 signals. Synergistic induction is mediated by two mechanisms: an enhanced rate of transcription and increased mRNA stability. In contrast to the regulation of IL-2 and IL-2R expression, which is inhibited by cyclosporin A-, but not rapamycin-dependent signal transduction pathways, CTLA-4 expression is inhibited by either cyclosporin A or rapamycin. Thus, synergistic induction of CTLA-4 expression requires both cyclosporin A- and rapamycin-dependent signals.
Finn
P W
PW
Department of Medicine, Brigham and Women's Hosptial, and Harvard Medical School, Boston, MA 02115, USA.
He
H
H
Wang
Y
Y
Wang
Z
Z
Guan
G
G
Listman
J
J
Perkins
D L
DL
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D018106:CD28 Antigens / Q000502:physiology*; D060908:CTLA-4 Antigen; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D018796:Immunoconjugates; D051379:Mice; D011090:Polyenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020123:Sirolimus; D014158:Transcription, Genetic / Q000187:drug effects
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D011090:Polyenes; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D016572:Cyclosporine; D003513:Cycloheximide; D020123:Sirolimus