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

Optimal T-cell activation requires both an antigen-specific signal delivered through the T-cell receptor and a costimulatory signal which can be delivered through the CD28 molecule. CD28 costimulation induces the expression of multiple lymphokines, including interleukin 2 (IL-2). Because the c-Rel transcription factor bound to and activated the CD28 response element within the IL-2 promoter, we focused our study on the mechanism of CD28-mediated regulation of c-Rel in human peripheral blood T cells. We showed that CD28 costimulation accelerated the kinetics of nuclear translocation of c-Rel (and its phosphorylated form), p50 (NFKB1), and p65 (RelA). The enhanced nuclear translocation of c-Rel correlated with the stimulation of Il-2 production and T-cell proliferation by several distinct anti-CD28 monoclonal antibodies. This is explained at least in part by the long-term downregulation of I kappa B alpha following CD28 signalling as opposed to phorbol myristate acetate alone. Furthermore, we showed that the c-Rel-containing CD28-responsive complex is enhanced by, but not specific to, CD28 costimulation. Our results indicate that c-Rel is one of the transcription factors targeted by CD28 signalling.
Mol Cell Biol 1994 Dec
PMID:Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells. 796 33

Sex steroid hormones play a role in the complex network of immune responses but the mechanism of their action is still unclear. Effects of a wide range of doses of 17 beta-estradiol (E2: 0.2-100 ng/ml) on human tonsillar lymphocyte cultures were examined. B and T lymphocyte enriched preparations were stimulated with various concentrations of interleukin-2 and the production of immunoglobulin was measured. Addition of E2 increased B cell immunoglobulin production in a T cell dependent way with intact T cells being obligatory. The effects of E2 were also examined on DNA synthesis by tonsillar T cells. E2 alone caused a significant increase in T cell DNA synthesis. With phytohaemagglutinin-stimulated T cell cultures there was a significant increase in DNA synthesis with E2 at pharmacological doses. Different cell surface and activation markers (including CD25, p75, HLA-DR, CD28) on tonsillar lymphocytes were also studied after exposure to E2. The presence of E2 made no significant difference in the expression of the markers either alone or when the activation antigens were induced by other stimuli. We have shown that intact T cells are needed for the action of E2 on tonsillar B lymphocyte differentiation and have excluded several mechanisms of action of E2 since common activation antigens are unaffected.
J Steroid Biochem Mol Biol 1994 Feb
PMID:Effect of 17 beta-estradiol on immunoglobulin secretion by human tonsillar lymphocytes in vitro. 814 92

T-cell activation requires two signaling events. One is provided by the engagement of the T-cell antigen receptor, and the second represents a costimulatory signal provided by antigen-presenting cells. CD28 mediates a costimulatory signal by binding its ligands, B7-1 and B7-2, on antigen-presenting cells, but the signaling pathway activated by CD28 has not been identified. A homologous molecule, CTLA-4, expressed on activated T cells, also binds to B7-1 and B7-2, but whether it has a signaling function is not known. We performed a structure-function analysis of CD28 to identify the functional domain which activates signal transduction. Truncation of the 40-amino-acid CD28 cytoplasmic tail abrogated costimulatory signaling. Chimeric constructs containing the extracellular and transmembrane regions of CD8 linked to the cytoplasmic region of CD28 had a costimulatory signaling function. Similar chimeras containing the cytoplasmic tail of CTLA-4 did not signal. Thus, the cytoplasmic region of CD28, but not CTLA-4, is sufficient to mediate costimulatory signaling. In addition, after CD28 stimulation, the p85 subunit of phosphatidylinositol 3'-kinase and phosphatidylinositol 3'-kinase activity were found in CD28 immunoprecipitates. The CD8-CD28 chimera, which has a costimulatory signaling function, associates with p85, while the nonfunctioning CD8-CTLA-4 chimera and a CD8-zeta chimera do not associate with p85. These results suggest that phosphatidylinositol 3'-kinase is specifically activated by CD28 and may mediate proximal events in the costimulatory signaling pathway regulated by CD28.
Mol Cell Biol 1994 May
PMID:The cytoplasmic domain of CD28 is both necessary and sufficient for costimulation of interleukin-2 secretion and association with phosphatidylinositol 3'-kinase. 816 87

CD28 is a 44 kDa Ig superfamily cell surface molecule expressed on most mature T cells. Through its interaction with the recently identified B7/BB1 counter-receptor, it is believed to play an important role as a co-stimulator of T cells along with the TCR-CD3 complex. Activation of T cells with CD28 mAbs synergizes with TCR-CD3 and CD2 stimulation, resulting in long term T cell proliferation, differentiation of cytotoxic T cells and production of large amounts of cytokines. In order to further delineate the role of CD28 in signal transduction and T cell activation, human CD28 was transfected into CD3+ murine T cell hybridomas. High levels of cell surface CD28 expression was achieved by protoplast fusion. The transfected molecule retained all the native CD28 mAb epitopes found on human T cells. In these transfectants, CD28 mAbs, similarly to CD3 mAbs, were able to induce Ca2+ mobilization, IL-2 promoter induction (measured as beta-galactosidase activity in T cells hybridomas pre-transfected with the IL-2-lac Z reporter gene), IL-2 secretion, TNF alpha production and apoptosis (observed as growth arrest and genome fragmentation). The parental host cells, or cells transfected with vector alone, responded only to mAbs to CD3. IL-2 secretion in the transfectants was obtained using either an IgM mAb to CD28 or IgG mAbs presented on the surface of IgG-FcR+ B lymphoma cells. Optimal activation via CD28 was inhibited by suboptimal concentrations of soluble CD3 mAb, suggesting an interaction between the two pathways. The immunosuppressive drugs Cyclosporin A and FK506 completely blocked CD28 and CD3 mediated IL-2 production in these transfectants whereas rapamycin had only a partial inhibitory effect. Finally, since the transfected human CD28 molecule confers full functional responsiveness to the murine T cell hybridomas without the need for costimulators such as PMA, this model is ideal for studying the structure-function relationships of the CD28 molecule as well as the transmembrane and cytoplasmic associations implied in CD28 signaling.
Mol Immunol 1994 Jan
PMID:Functional expression of human CD28 in murine T cell hybridomas. 830 98

At least three stages in the intrathymic development of pre-T cells are demarcated by differences in the competence to express the interleukin-2 (IL-2) gene as an acute response to stimulation. IL-2 inducibility appears to be acquired relatively early, prior to T-cell receptor (TcR) gene rearrangement. It is then abrogated during the stage when cells are subject to positive and negative selection, i.e., the fate determination processes that select cells for maturation or death. IL-2 inducibility finally reappears in mature classes of thymocytes that have undergone positive selection. To provide a basis for a molecular explanation of these developmental transitions, we have examined the representation in different thymocyte subsets of a set of DNA-binding proteins implicated in IL-2 gene regulation. As the DNA-binding activities of many factors are elicited only by inductive stimuli, the cells were cultured in the presence or absence of the calcium ionophore A23187 and phorbol ester. Our results separate these factors into four regulatory classes: (i) constitutive factors, such as Oct-1 and probably Sp1, that are expressed in thymocytes at all stages; (ii) inducible factors, such as NF-kappa B and complexes binding to the region of a CD28 response element, that can be activated in all thymocytes, including those cells (CD4+ CD8+ TcRlow) that can undergo selection; (iii) inducible factors, such as NF-AT and AP-1, that can be activated in mature (CD4+ CD8- TcRhigh) and immature (CD4- CD8- TcR-) thymocytes alike but not in the transitional stages when the cells (CD4+ CD8+ TcRlow) are subject to selection; and (iv) a factor containing CREB, which can be activated in thymocytes of all developmental stages by culture but does not require specific induction. These results verify that inducible transcription factors are targets of intrathymic developmental change. They also identify NF-AT and AP-1 as factors that are particularly sensitive to the mechanism altering thymocyte responses during the stages when thymocytes may undergo positive and negative selection.
Mol Cell Biol 1993 Jan
PMID:Molecular basis for developmental changes in interleukin-2 gene inducibility. 841 28

T-cell activation involves two distinct signal transduction pathways. Antigen-specific signaling events are initiated by T-cell receptor recognition of cognate peptide presented by major histocompatibility complex molecules. Costimulatory signals, which are required for optimal T-cell activation and for overcoming the induction of anergy, can be provided by the homodimeric T-cell glycoprotein CD28 through its interaction with the counterreceptors B7-1 and B7-2 on antigen-presenting cells. Ligation of CD28 results in its phosphorylation on tyrosines and the subsequent recruitment and activation of phosphatidylinositol 3-kinase (PI 3-kinase). It has been suggested that the induced association of CD28 and PI 3-kinase is required for costimulation. We report here that ligation of CD19, a heterologous B-cell receptor that also associates with and activates PI 3-kinase upon ligation, failed to costimulate interleukin-2 production. Moreover, pharmacological inhibition of PI 3-kinase activity failed to block costimulation mediated by CD28. By mutational analysis, we demonstrate that disruption of PI 3-kinase association with CD28 also did not abrogate costimulation. These results argue that PI 3-kinase association with CD28 is neither necessary nor sufficient for costimulation of interleukin-2 production. Finally, we identify specific amino acid residues required for CD28-mediated costimulatory activity.
Mol Cell Biol 1995 Dec
PMID:CD28-mediated costimulation in the absence of phosphatidylinositol 3-kinase association and activation. 852 48

We find that interleukin-2 (IL-2) production is severely depressed (80-90%) in AIDS T-cells (CD4+ or CD8+) stimulated with anti-CD3 or Con A together with phorbol ester (PMA) or anti-CD28 coactivation. Likewise, the proliferative response of CD4+ T-cells was suppressed, from a mean of 24.6% (HIV+) to 59.1% (AIDS) for PMA with activators OKT3 (anti-CD3), Con A, enterotoxin B or pokeweed mitogen, and 20.2% (HIV+) to 77.8% (AIDS) with anti-CD28 co-activation. Similar degrees of suppression were found with the CD8+ T-cells except for a much greater suppression at the HIV+ stage with anti-CD28 (57.7%), approximately 2.5 times higher than for PMA coactivation. However, when proliferation was induced by the two coactivators combined (PMA plus anti-CD28), much less suppression was observed: 8.5% (HIV+) to 19.0% (AIDS) for CD4+ cells and 8.2% to 26.5%, respectively, for CD8+ cells. The data suggest that during HIV infection the CD28 pathway becomes most defective, but can be bypassed to some extent by the less-impaired PMA pathway. The IL-2 (+PMA) signal in HIV+ and AIDS cells was also significantly less suppressed suggesting that the disregulation in HIV infection is more prominent prior to the IL-2 stage of the mitogenic pathway. It is remarkable that the CD4+ and CD8+ T-cells at both the HIV+ and AIDS stages generally show the same degree of suppression with all the various activators and coactivators used.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Mol Biol (Noisy-le-grand) 1995
PMID:Suppressed proliferative response and interleukin-2 production in hispanic HIV+ and AIDS T-cell subsets. 857 45

We find that purified CD4+ T cells from 30 HIV+ individuals have a suppressed Interleukin-4 (IL-4) production compared to normal controls regardless of activator (anti-CD3 or Con A) or co-activator [phorbol ester (PMA or anti-CD28)], generally by 2-4 fold. In every case, the cells producing IL-4 respond more strongly to anti-CD28 co-activation than to PMA, ie, 1150 pg/ml compared to 2070 pg/ml for controls and 398 pg/ml compared to 1250 pg/ml for HIV+ cells, respectively. In contrast, anti-CD3 with PMA gives a more vigorous IL-2 response than with anti-CD28, ie, 37.3 ng/ml compared to 12.3 ng/ml for controls and 28.5 ng/ml versus 15.1 ng/ml for HIV+ cells, respectively. These data are not compatible with the TH1/TH2 switch hypothesis since IL-4 production is decreased, not increased for CD4+ HIV+ T-cells and while IL-2 production is decreased with PMA, it is not decreased significantly with anti-CD28. Interestingly, 5 mM N-acetylcysteine (NAC) acts as an immunoenhancer; mitogenesis was enhanced 2 fold or more in general for control and HIV+ CD4+ T-cells and IL-2 production was enhanced 2-3 fold for anti-CD3 (with PMA or anti-CD28) for both controls and HIV+ CD4+ cells. However, NAC suppressed IL-4 production induced by anti-CD3 and anti-CD28 in both control and HIV+ CD4+ T cells. In the other cases, it produced in general no significant change.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Mol Biol (Noisy-le-grand) 1995
PMID:N-acetylcysteine (NAC) enhances interleukin-2 but suppresses interleukin-4 secretion from normal and HIV+ CD4+ T-cells. 857 46

IL-2 and IFN-gamma gene expression was analyzed using an original method for in situ hybridization (ISH) with non-isotopic probes and flow cytometric analysis (FC). This method permits rapid detection of mRNA at a single cell level among in vitro activated human peripheral blood mononuclear cells (PBMC) and purified CD4 and CD8 T cell subsets. After stimulation with PMA and ionomycin (PMA+Io), cells were fixed at different times and hybridized with digoxigenin (DIG)-labelled RNA antisense or sense probes specific for IL-2 and IFN-gamma. The level of cytokine gene expression in individual cells was visualized using FITC-conjugated anti-DIG antibodies and the fluorescent signal was analyzed by flow cytometry. Specific hybridization with IL-2 and IFN-gamma antisense probes was detected among activated PBMC within lymphoid cells identified by their light scattering properties. Kinetic analysis of the frequency of mRNA producing cells exhibited a biphasic pattern with an early peak at 6-8 hrs. when percentages of IL-2 and IFN-gamma expressing cells reached 35 +/- 7% and 18 +/- 4%, respectively. Similar data were obtained by enzymatic detection on cell smears using AP-conjugated anti-DIG. Combination of ISH with FC was applied to the comparison of the pattern of cytokine gene expression between CD4 and CD8 T cell subsets isolated by negative selection using immunobeads and magnetic separation. IL-2 was expressed by activated CD8 T cells (25-35%), but CD4 T cells were the major producers of IL-2 as assessed by the high frequency of mRNA expressing cells (60%) and the large amount of mRNA per cell relative to the mean fluorescence intensity. In contrast, IFN-gamma mRNA was preferentially expressed by CD8 T cells (27-37%) and a minority of CD4 T cells (17-23%). Despite quantitative differences, kinetic analysis of IL-2 gene expression in CD4 and CD8 T cells showed similar profiles with an early peak at 6-8 hrs. Upregulation of IL-2 gene expression in CD4 T cells by CD28 co-stimulation increases the amount of IL-2 mRNA per cell as visualized by mean fluorescence intensity. In addition the effect of CD28 co-stimulation on IL-2 mRNA stabilisation was demonstrated by the maintenance of a high frequency of IL-2 expressing CD4 T cells and an elevated level of mRNA per cell for prolonged period after PMA+Io stimulation. By contrast CD28 co-stimulation had no obvious effect on IFN-gamma expression.
Cell Mol Biol (Noisy-le-grand) 1995 Nov
PMID:Distinct pattern of IL-2 and IFN-gamma gene expression in CD4 and CD8 T cells: cytofluorometric analysis at a single cell level using non-radioactive probes. 859 73

The present study compares the mitogen-activated protein (MAP) kinase responses in T cells activated with the CD28 ligands B7-1 (CD80) and B7-2/B70 (CD86). Ligands B7-1 and B7-2 do not activate the Raf-1/ERK2 cascade, but share the ability to activate related Jun kinases. These natural ligands for CD28 had no stimulatory effect alone on Jun kinase activation, but the data show that B7-1 and B7-2 could both co-operate with intracellular Ca2+ increase and protein kinase C (PKC) activation to stimulate Jun kinases. The present study shows that the interaction of CD28 with its ligands B7-1 and B7-2 can induce identical signal transduction through the MAP kinase cascades.
Mol Immunol 1996 Jan
PMID:CD28 signal transduction pathways. A comparison of B7-1 and B7-2 regulation of the map kinases: ERK2 and Jun kinases. 860 25


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