Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28.
T-cell activation results in the production of multiple lymphokines. Efficient lymphokine gene expression appears to require both T-cell antigen receptor (TCR) signal transduction and an uncharacterized second or costimulatory signal. CD28 is a T-cell differentiation antigen that can generate intracellular signals that synergize with those of the TCR to increase T-cell activation and interleukin-2 (IL-2) gene expression. In these studies, we have examined the effect of CD28 signal transduction on granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), and gamma interferon (IFN-gamma) promoter activity. Stimulation of CD28 in the presence of TCR-like signals increases the activity of the GM-CSF, IL-3, and IFN-gamma promoters by three- to sixfold. As previously demonstrated for the IL-2 promoter, the IL-3 and GM-CSF promoters contain distinct elements of similar sequence which specifically bind a CD28-induced nuclear complex. Mutation of the CD28 response elements in the IL-3 and GM-CSF promoters abrogates the CD28-induced activity without affecting phorbol ester- and calcium ionophore-induced activity. UV cross-linking indicates that the CD28-induced nuclear complex contains polypeptides of approximately 35, 36, and 44 kDa. These studies indicate that the TCR and CD28-regulated signal transduction pathways coordinately regulate the transcription of several lymphokines and that the influence of CD28 signals on transcription is mediated by a common complex.
Fraser
J D
JD
Department of Medicine, University of California, San Francisco 94143.
Weiss
A
A
D015703:Antigens, CD / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D001483:Base Sequence; D018106:CD28 Antigens; D004247:DNA; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D015458:Leukemia, T-Cell; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D017385:Sequence Homology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D007376:Interleukin-2; D007377:Interleukin-3; D008222:Lymphokines; D015759:Ionomycin; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA; D013755:Tetradecanoylphorbol Acetate