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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Mol Cell Biol 1992 Oct
PMID:Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28. 132 52

1. The purpose of these studies was to investigate the modulation of the proliferation of human T cells obtained from peripheral blood by dexamethasone (DEX), isoproterenol (ISO), and prostaglandin E2 (PGE2). The former two substances interact with T cells via the glucocorticoid and beta-adrenergic receptors respectively. When occupied by their natural ligands, glucocorticosteroids and catecholamines, these receptors have a role in modulating T-cell function during stress. During the inflammatory response increased levels of PGE2 bind to their receptors on T cells and thus alter responsiveness. Proliferation of T cells was induced by immobilized anti-CD3 monoclonal antibody (mAb) in the presence or absence of an additional costimulatory signal delivered by anti-CD28 mAb. 2. Various physiologic concentrations of DEX, ISO, or PGE2 were added at the time of initiation of the cultures and subsequent proliferation of the unstimulated T cells was determined. The results demonstrate that physiologic concentrations of all three of these agents inhibit the anti-CD3 mAb-induced proliferation of T cells. 3. Although DEX and PGE2 were equipotent in suppressing T-cell proliferation, ISO was much less effective. 4. Because concomitant elevations in the peripheral levels of these substances may occur, experiments were performed to determine the T-cell inhibitory effects of DEX together with either PGE2 or ISO. Synergistic suppression of T-cell proliferation was observed when various concentrations of DEX and PGE2, but not DEX and ISO, were added to cultures. This synergistic suppression could not be explained by an increase in cAMP accumulation in T cells stimulated with DEX and PGE2. 5. Finally, the addition of anti-CD28 mAb to anti-CD3 mAb-stimulated T cells overcame much of the suppression of proliferation induced by PGE2 or ISO but less so than that induced by DEX.
Cell Mol Neurobiol 1992 Oct
PMID:Inhibition of anti-CD3 monoclonal antibody-induced T-cell proliferation by dexamethasone, isoproterenol, or prostaglandin E2 either alone or in combination. 133 6

The regulation of early and late events of T cell activation via the CD28 molecule has been investigated, using as an indicator system the differentiated leukemic T cell line Jurkat. Both CD3 and CD28 mAbs induced an increase in (Ca2+)i in Jurkat cells, although with different kinetics, the latter being slower than the former. CD28-mediated (Ca2+)i mobilization was highly sensitive to cholera toxin (ID50 25 ng/ml, vs 300 ng/ml for CD3 stimulation). The inhibitory action of cholera toxin was neither merely due to the increase in intracellular cAMP concentrations, nor to decrease in cell surface expression of the CD28 molecule. To evaluate the effects of cholera toxin on late events of Jurkat cell activation induced by CD28 and CD3 mAbs, the action of cholera toxin and cAMP and CD3- and CD28-mediated IL-2 secretion was analyzed. CD3-induced IL-2 secretion was highly sensitive to cholera toxin (ID less than 5 ng/ml); on the other hand, CD28-induced IL-2 secretion was poorly sensitive to cholera toxin, in sharp contrast to (Ca2+)i mobilization. On the basis of these data, it is hypothesized that the CD28 pathway could be associated with at least two distinct transduction mechanisms, one responsible for the (Ca2+)i rise in Jurkat cells and highly sensitive to cholera toxin, and the other, whose second messenger is unknown, resistant to cholera toxin and responsible for IL-2 secretion.
Mol Immunol
PMID:Dissociation between early and late events in T cell activation mediated through CD28 surface molecule. 164 71

The delivery of a mitogenic signal to T cells via any one of several cell surface molecules elicits a variety of intracellular responses, some or all of which regulate subsequent gene expression events. The expression of nine novel mitogen-induced genes in response to various T-cell-activating agents was examined to evaluate the diversity of pathways which regulate such genes. The relative contribution of distinct secondary signals, individually or together, to mitogen-stimulated gene induction and the capability of individual genes to respond to the sometimes divergent signals generated from different cell surface structures is addressed. The activation of T cells with mitogenic monoclonal antibodies directed against the CD2 or CD3 cell surface molecules, or with phytohemagglutinin, induced all nine genes. Thus, stimulation by fully mitogenic agents regardless of cell surface-binding specificity correlated with the expression of all of the genes studied. However, heterogeneous patterns of gene expression, encompassing five regulatory classes, were revealed by the use of phorbol 12-myristate 13-acetate, calcium ionophore, and anti-CD28 monoclonal antibody, agents which mediated only a subset of intracellular events and thus an incomplete mitogenic signal. Interleukin-2 and two novel lymphokines represented one regulatory class that appeared to require unique transcriptional activation signals relative to the other mitogen-induced genes. As demonstrated in the accompanying paper (P. F. Zipfel, S. G. Irving, K. Kelly, and U. Siebenlist, Mol. Cell. Biol. 9:1041-1048, 1989), the immediate transcriptional response of T cells to mitogenic stimulation is quite complex, involving numerous genes beyond those which have been previously described. Furthermore, the discrimination of several regulatory phenotypes among these nine genes suggests that a multiplicity of signaling pathways extends from the cell surface to the level of transcription.
Mol Cell Biol 1989 Mar
PMID:Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation. 256 6

CD28 is a homodimeric glycoprotein expressed on the surface of a major subset of human T cells that has recently been identified as a member of the immunoglobulin supergene family. The binding of monoclonal antibodies to the CD28 antigen on purified T cells does not result in proliferation; however, previous studies have shown that the combination of CD28 stimulation and protein kinase C activation by phorbol myristate acetate (PMA) results in T-cell proliferation that is independent of both accessory cells and activation of the T-cell receptor-CD3 complex. In the present study, effects of stimulation by anti-CD28 on cell cycle progression and on the interleukin 2 (IL-2) and IL-2 receptor system have been investigated on primary cultures of purified peripheral-blood CD28+ T cells. There was no measurable effect on cell size or on DNA synthesis after stimulation of resting (G0) cells by CD28 alone. After 3 h of activation of T cells by PMA alone, a slight (8%) increase in cell volume occurred that did not progress to DNA synthesis. In contrast, T-cell stimulation by CD28 in combination with PMA resulted in a progressive increase in cell volume in approximately 100% of cells at 12 to 14 h after stimulation. Northern blot (RNA blot) analysis revealed that CD28 stimulation alone failed to cause expression of the alpha chain of the IL-2 receptor or of IL-2 mRNA, and in accord with previous studies, stimulation by PMA alone resulted in the accumulation of IL-2 receptor transcripts but no detectable IL-2 mRNA. In contrast, T-cell stimulation by the combination of CD28 and PMA resulted in the appearance of IL-2 transcripts and enhanced expression of IL-2 receptor mRNA. Functional studies revealed that the proliferation induced by CD28 and PMA stimulation was entirely resistant to cyclosporine, in contrast to T-cell activation induced by the CD3-T-cell receptor complex. Cyclosporine was found not to affect the accumulation of IL-2 mRNA after CD28 plus PMA stimulation, although there was no detectable IL-2 mRNA after stimulation by CD3 in the presence of the drug. Furthermore, stimulation by CD28 in combination with immobilized CD3 antibodies caused a striking enhancement of IL-2 mRNA expression that was, in part, resistant to the effects of cyclosporine. These studies indicate that the CD28 molecule synergizes with protein kinase C activation to induce IL-2 gene expression and demonstrate that stimulation by the CD28 pathway can cause vigorous T-cell proliferation even in the presence of cyclosporine and that cyclosporine does not prevent transcription of 16-2 mRNA, as has been suggested previously. Moreover, these findings suggest that a potential role for the CD28 molecule in vivo may be to augment IL-2 production after stimulation of the CD3-T-cell receptor molecular complex and thereby to amplify an antigen-specific immune response. Finally, these results provide further evidence that the CD28 molecule triggers T-cell proliferation in a manner that differs biochemically from CD3-T-cell receptor-induced proliferation.
Mol Cell Biol 1987 Dec
PMID:T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. 283 Apr 95

Signal transduction occurs through multiple receptors expressed on mature, resting T cells. In addition to the CD3-T cell receptor complex, the CD2, CD4, CD5, CD7, CD8 and CD28 receptors mobilize cytoplasmic calcium within minutes of binding with monoclonal antibodies and additional crosslinking occurs on the cell surface. As an approach to study the interactions between these receptors and their transduced signals, monoclonal antibodies to each of these receptors were covalently coupled as heteroconjugates and investigated for activity in cytoplasmic calcium mobilization using indo-1 and flow cytometry. Of a total of 35 conjugates studied, there were seven heteroconjugates that showed an increase in activity and these consisted of either certain conjugates of anti-CD3 or certain conjugates of anti-CD5. The CD3-CD2, CD3-CD4, CD3-CD6 and CD3-CD8 heteroconjugates each gained two to three orders of magnitude in titer in calcium mobilization compared to unconjugated CD3 or the CD3-CD3 conjugate. The increase in activity was not accompanied by an increase in binding titer, indicating that signal transduction occurred at lower levels of receptor occupancy. The increased activity was dependent in each case on the relevant second receptor, since unconjugated CD2, CD4, CD6 or CD8 MAb could block the activity of the corresponding heteroconjugate. Neither CD3-CD5, CD3-CD28 or CD3-CD3 conjugates gained activity, whereas CD3-CD7 heteroconjugates gained slightly in activity. The heteroconjugates with CD5 that acquired ability to mobilize calcium at low concns (less than 5 micrograms/ml) were CD5-CD4, CD5-CD8 and CD5-CD6. Their activity could be inhibited by either CD5 MAb or the second MAb of the heteroconjugate. The increased activity of CD3 or CD5 heteroconjugates was observed in the absence of extracellular calcium. Size exclusion chromatography of heteroconjugates demonstrated that 1:1 ratios were optimal, but larger conjugates were also active. These results suggest that certain receptors are capable for molecular interactions on the cell surface to form complexes with enhanced activity in signal transduction leading to calcium mobilization.
Mol Immunol 1989 Feb
PMID:Enhanced transmembrane signalling activity of monoclonal antibody heteroconjugates suggests molecular interactions between receptors on the T cell surface. 291 58

T-cell receptor (TCR) signalling is required to induce expression of the interleukin 2 (IL-2) gene in mouse T cells. Additional costimulation through CD28 augments IL-2 production by 30- to 100-fold. Using IL-2 RNA accumulation and transcription reporter assays, we have addressed potential mechanisms of CD28 regulation at various time points of stimulation. The kinetic regulation of IL-2 mRNA by TCR and CD28 signals is complex: (i) at the earliest detectable time point, CD28 signalling causes a 20-fold increase compared with TCR signalling alone; (ii) both groups rapidly accumulate mRNA for the first 4 h; (iii) IL-2 mRNA then disappears from cells stimulated through the TCR alone but plateaus or increases slightly in cells costimulated through CD28; and (iv) after 8 h, the mRNA disappears in cultures with the anti-CD28 antibody. Transcription reporter assays did not show a specific effect of CD28 signalling on IL-2 enhancer driven transcription. This was true for either a 353- or a 1.9-kb enhancer, over a broad range of kinetics and TCR occupancy, and with several TCR signal mimics. The early component of CD28 costimulation is nuclear, however, since the initial enhancement of mRNA is also found in unspliced IL-2 RNA. Between 2 and 6 h, there is a marked difference in the rates of decay of IL-2 mRNA in the presence and absence of the CD28 signalling. Rapid decay of IL-2 mRNA commences after 8 h even in the presence of CD28 signals, although the decay occurs at a rate slower than that seen after 4 h of anti-TCR stimulation alone. This complexity suggests the existence of two interesting molecular mechanisms by which CD28 costimulates lymphokine gene expression.
Mol Cell Biol 1995 Jun
PMID:Regulation of interleukin 2 gene expression by CD28 costimulation in mouse T-cell clones: both nuclear and cytoplasmic RNAs are regulated with complex kinetics. 753 4

We report the in vitro biological characterization of WIN 17317-3 (1-benzyl-7-chloro-4-n-propylimino-1,4-dihydroquinoline hydrochloride), a novel inhibitor of voltage-activated (n-type) K+ channels in human T lymphocytes. WIN 17317-3 inhibits 125I-charybdotoxin binding to n-type K+ channels with an IC50 value of 83 +/- 4 nM. WIN 17317-3 demonstrates competitive inhibition of 125I-charybdotoxin binding by increasing its dissociation constant without changing the total number of channels bound and by having no effect on its dissociation rate constant. WIN 17317-3 inhibits whole-cell, n-type K+ currents with characteristics indicative of open channel block and has an IC50 value of 335 nM. The compound is 150-fold selective for n-type K+ channels, compared with Ca(2+)-activated, charybdotoxin-sensitive K+ channels in smooth muscle. In purified CD4+ T lymphocytes activated with either anti-CD3 plus phorbol ester or anti-CD3 plus anti-CD28, WIN 17317-3 decreases interleukin-2 production with EC50 values of 0.8 microM and 1 microM, respectively. WIN 17317-3 is a novel, potent, and selective nonpeptide n-type K+ channel antagonist that inhibits interleukin-2 production in human T lymphocytes.
Mol Pharmacol 1995 Jul
PMID:WIN 17317-3: novel nonpeptide antagonist of voltage-activated K+ channels in human T lymphocytes. 754 39

The transcription factors NFAT and AP-1 have been shown to be essential for inducible interleukin-2 (IL-2) expression in activated T cells. NFAT has been previously reported to bind to two sites in the IL-2 promoter: in association with AP-1 at the distal antigen response element at -280 and at -135. On the basis of DNase I footprinting with recombinant NFAT and AP-1 proteins, gel shift assays, and transfection experiments, we have identified three additional NFAT sites in the IL-2 promoter. Strikingly, all five NFAT sites are essential for the full induction of promoter activity in response to T-cell receptor stimulation. Four of the five NFAT sites are part of composite elements able to bind AP-1 in association with NFAT. These sites display a diverse range of cooperativity and interdependency on NFAT and AP-1 proteins for binding. One of the NFAT sites directly overlaps the CD28-responsive element. We present evidence that CD28 inducibility is conferred by the AP-1 component in NFAT-AP-1 composite elements. These findings provide further insight into the mechanisms involved in the regulation of the IL-2 promoter.
Mol Cell Biol 1995 Nov
PMID:Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T-cell receptor stimulation. 756 83

T-cell activation requires two different signals. The T-cell receptor's recognition of a specific antigen on antigen-presenting cells provides one, and the second signal comes from costimulatory molecules such as CD28. In contrast, T cells that are stimulated with antigen in the absence of the CD28 costimulatory signal can become anergic (nonresponsive). The CD28 response element (CD28RE) has been identified as the DNA element mediating interleukin 2 (IL-2) gene activation by CD28 costimulation. Our previous work demonstrates that the Rel/NF-kappa B family proteins c-Rel, RelA (p65), and NFKB1 (p50) are involved in the complex that binds to the CD28RE. We also showed that c-Rel, but not NFKB1 (p50), can bind to the CD28RE and activate CD28RE-driven transcription in cotransfection assays. However, the role of RelA (p65) in CD28 signaling has not yet been addressed. We provide evidence that RelA (p65) itself bound directly to the CD28RE of the IL-2 promoter and other lymphokine promoters. In addition, RelA (p65) was a potent transcriptional activator of the CD28RE in vivo. We show that a RelA (p65)-c-Rel heterodimer bound to the CD28RE and synergistically activated the CD28RE enhancer activity. We also demonstrate that activated Raf-1 kinase synergized with RelA (p65) in activating the CD28RE enhancer activity. Interestingly, a soluble anti-CD28 monoclonal antibody alone, in the absence of other stimuli, also synergized with RelA (p65) in activating the CD28RE. Furthermore, we show that RelA (p65) activated expression of the wild-type IL-2 promoter but not the CD28RE-mutated IL-2 promoter. A combination of RelA (p65) and NFKB1 (p50) also activated the IL-2 promoter through the CD28RE site. These results demonstrate the functional regulation of the CD28RE, within the IL-2 promoter, by Rel/NF-kappa B transcription factors.
Mol Cell Biol 1995 Aug
PMID:RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter. 762 20


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