Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

CD28, which is a member of the immunoglobulin superfamily of molecules (IgSF), is a homodimer of two polypeptides containing a single V-like domain with short transmembrane and cytoplasmic regions. It serves as a co-signalling molecule for T cell activation through binding to its cognate counter-receptors CD80 and B70, expressed on antigen presenting cells. In the current study, we investigated the regions of CD28 which are involved in its interactions with CD80 and B70, using site directed mutagenesis, CD28 mAb epitope mapping, receptor based adhesion assays and direct binding of Ig-fusion proteins to cell surface receptors. Truncation or substitution of a stretch of a proline rich "hallmark" sequence, "MYPPPY", abrogates binding to CD80 or B70, while retaining CD28 mAb epitopes and cell surface expression. On an Ig-fold model of the CD28 V-domain, this fully conserved motif localizes to a CDR3-like region. Mutations introduced into other loops, including the CDRI-like and CDR2-like regions, had very little effect on CD80 or B70 binding. Mutations introduced within the predicted beta-strand regions caused loss of receptor expression. Conservative substitution of both the flanking tyrosine residues within the "MYPPPY" motif with phenylalanine, caused loss of binding to B70 but not to CD80. These results show that, although the same overall region on CD28 may be involved in the interactions with CD80 and B70, subtle but important differences distinguish recognition by the two molecules. These finding, along with previous observations on the differential pattern of expression and tissue distribution of CD80 and B70, support the contention that these molecules play distinct roles in the regulation of immune responses in vivo.
Mol Immunol 1996 Feb
PMID:Differential recognition by CD28 of its cognate counter receptors CD80 (B7.1) and B70 (B7.2): analysis by site directed mutagenesis. 864 53

The binding of CD40 ligand on activated T cells to CD40 on resting B cells induces the expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86). The induction of B7 molecules by CD40 ligand-CD40 interaction represents a critical step in rendering B cells competent for antigen presentation. The CBA/N mouse has a defect in CD40 signalling which has been attributed to a mutation in Bruton's tyrosine kinase. We have compared the ability of murine CD40 ligand to induce B7-1 and B7-2 expression on B cells isolated from CBA/N and wild-type CBA/J mice. We find that the CBA/N defect partially impairs both B7-1 and B7-2 induction via CD40. Subsequent experiments investigated the roles of different second messenger systems in B7-1 and B7-2 induction in normal B cells. In M12 B lymphomas either CD40 cross-linking or cAMP treatment can induce B7 molecules. Here we report that treatment with dibutyryl-cAMP also induces B7 molecules in normal B cells provided that they have been preactivated by CD40 cross-linking. We also find that PMA and ionomycin treatment of B cells induces B7-2 but not B7-1 expression. Our data therefore show roles for BTK, cAMP and PMA/ionomycin in B7 induction, as well as providing further evidence for differential regulation of B7-1 and B7-2 induction in B cells.
Mol Immunol 1996 Apr
PMID:Induction of costimulatory molecules B7-1 and B7-2 in murine B cells. the CBA/N mouse reveals a role for Bruton's tyrosine kinase in CD40-mediated B7 induction. 870 Jan 70

The metastatic process is characterized by a complex series of sequential steps involving constant interactions (mutual "cross-talks") of metastasized tumor cells with their microenvironment (lymphocyte, macrophages, endothelial cells, etc.) in target organs. These interactions determine the outcome of metastasis (either the eradication of metastatic cells or their increased proliferation and invasion). Recently developed methods of tumor and host cell analysis at the molecular level allow better elucidation of molecular mechanisms of metastasis and of immune mechanisms involved in antitumor responses. Direct modulation of these processes will probably increase the success of clinical cancer treatment. Here we review data (a) on the expression of some costimulatory (MHC class II, CD80, sialoadhesin) and adhesion (LFA-1, ICAM-1, VLA-4) molecules on both metastasized tumor cells and host cells and (b) on the production of a cytotoxic molecule, nitric oxide, by in situ activated Kupffer and endothelial cells in the process of liver metastasis. This study was performed with well-characterized murine ESbL T lymphoma cells transduced with the bacterial lacZ gene, which allows detection and quantification of metastases at the single cell level throughout lymphoma growth and metastasis. Experimental results are discussed in the context of recent literature.
J Mol Med (Berl) 1996 Jul
PMID:New insights into tumor-host interactions in lymphoma metastasis. 884 48

We have characterized the regulation of nuclear factors involved in transcriptional control of the interleukin-2 (IL-2) promoter-enhancer activity in Jurkat T cells stimulated with superantigen presented on HLA-DR transfectants combined with the ligands LFA-3 (CD58) and B7-1 (CD80). Gel shift analyses showed that NF-AT was strongly induced in LFA-3-costimulated Jurkat T cells, suggesting that NF-AT is a key target nuclear factor for the CD2-LFA-3 pathway. Studies using HLA-DR-B7-1-LFA-3 triple transfectants showed that the LFA-3-induced NF-AT DNA binding activity was negatively regulated by B7-1 costimulation. In contrast, induction of a CD28 response complex containing only c-Rel proteins was seen after B7-1 costimulation. Both LFA-3 costimulation and B7-1 costimulation induced the AP-1 and NF-kappaB nuclear factors. Distinct compositions of the NF-AT complexes were seen in B7-1- and LFA-3-costimulated cells. LFA-3 induced primarily Jun-D, Fra-1, and Fra-2, while B7-1 induced June-D-Fos complexes. In contrast, AP-1 and NF-kappaB complexes induced in B7-1- and LFA-3-costimulated T cells showed similar contents. Transient transfection of Jurkat T cells with a construct encoding the IL-2 enhancer-promoter region (position -500 to +60) linked to a luciferase reporter gene revealed that B7-1 costimulation was required to induce strong transcriptional activity. Combined B7-1-LFA-3 costimulation resulted in a synergistic increase in IL-2 transcriptional activity. Multimers of the AP-1, NF-AT, NF-kappaB, and CD28 response elements showed distinct kinetics and activity after LFA-3 and B7-1 costimulation and revealed that B7-1 and LFA-3 converge to superinduce transcriptional activity of the AP-1, NF-AT, and CD28 response elements. Transcriptional studies with an IL-2 enhancer-promoter carrying a mutation in the CD28 response element site revealed that the activity was reduced by 80% after B7-1 and B7-1-LFA-3 costimulation whereas the transcriptional activity induced by LFA-3 was unaffected. Our data strongly suggest a selectivity in induction of nuclear factors by the CD2-LFA-3 and CD28-B7-1 pathways. This selectivity may contribute to regulation of the levels of IL-2 induced by LFA-3 and B7-1 costimulation and favor autocrine and paracrine T-cell responses, respectively.
Mol Cell Biol 1997 Mar
PMID:Costimulation by B7-1 and LFA-3 targets distinct nuclear factors that bind to the interleukin-2 promoter: B7-1 negatively regulates LFA-3-induced NF-AT DNA binding. 903 58

Lung dendritic cells (DCs) from mice were enriched to 92-99% purity using a multistep enrichment protocol which included fluorescence-activated cell sorting. DCs were analyzed for expression of cell surface molecules, function in a mixed leukocyte reaction (MLR), and dependence on accessory molecules in stimulating an MLR. DCs possessed potent accessory properties in vitro, while interstitial macrophages (IM), which are Ia-negative, displayed little MLR-stimulating function of their own. However, IM were capable of enhancing DC-initiated T cell proliferation via a cell contact mechanism. These results indicated that murine lung DCs functioned as stimulators of primary T cell responses, and that cells in the local environment influenced their function. Lung DCs expressed surface molecules typical of DCs from other sites including CD11a, CD54, CD80, and CD86. As is true for DCs in other sites, costimulatory molecules including CD80, CD86, CD40L, CD2, CD54, and CD11a played important roles in lung DC-initiated T cell proliferation. Interestingly, anti-CD86 monoclonal antibody (mAb) had little inhibitory effect on the MLR unless it was added in combination with anti-CD80 mAb. These studies suggest that CD80 on lung DCs can provide a costimulatory signal to allogeneic T cells in the absence of CD86 signaling, but that CD86 functions poorly except when CD80 is also engaged.
Am J Respir Cell Mol Biol 1997 Mar
PMID:Characterization of accessory molecules in murine lung dendritic cell function: roles for CD80, CD86, CD54, and CD40L. 930 14

Alveolar macrophages (AM) from sarcoid patients have been shown to be good antigen presenting cells (APC) unlike normal AM which are usually ineffective. We demonstrate in ten consecutive sarcoid patients that most of their AM, unlike normal AM, do coexpress high levels of CD86, CD40, and CD30L, all known to be important for T-cell activation. CD80 is also slightly more expressed on sarcoid AM than on normal AM, but is detected on only 26 +/- 6% (mean +/- SEM) of sarcoid AM. A good correlation is present between the percentage of sarcoid AM expressing CD86 and CD40 or CD86 and CD30L. However, no correlation is found between the percentage of CD80 and CD86 positive AM in these same patients. Blocking antibodies against CD86 were able to reduce by more than 80% allogeneic T-cell proliferation induced by the AM of sarcoid patients. This study provides evidence that AM can, in pathologic states such as sarcoidosis, express functional costimulatory molecules for T-cell activation such as CD86, thought to be rather specific for more professional APC such as dendritic cells.
Am J Respir Cell Mol Biol 1997 Jul
PMID:Alveolar macrophages in sarcoidosis coexpress high levels of CD86 (B7.2), CD40, and CD30L. 922 14

Seven random peptide libraries (two displaying linear peptides and five displaying cysteine-constrained peptides) were constructed as gene III fusion proteins of the bacteriophage fd-tet. These libraries were used to screen a blocking monoclonal antibody raised against B7-1 (CD80), a human cell surface antigen that binds two T cell receptors, CD28 and CTLA-4. After three rounds of screening against the immobilized antibody, 1000-fold enrichment was observed in libraries displaying both linear and cysteine-constrained peptides. DNA sequencing of the enriched phage revealed two distinct consensus sequences: HXG(A/Y)XH and DVCXXGGPGC. Phage expressing these consensus sequences bound to L307.4 but not to an isotype matched antibody, indicating that binding was antibody specific. Synthetic peptides corresponding to both motifs inhibited phage binding to L307.4, indicating that the gene III protein is not required for peptide binding. In addition, the cyclized forms of synthetic peptides containing the DVCXXGGPGC motif were capable of inhibiting L307.4 binding to soluble B7-1/Fc fusion. Moreover, phage expressing only the HXG(A/Y)XH consensus sequence were inhibited from binding to L307.4 by the presence of chelating agents. These results indicate that the framework within which the peptide is presented on the surface of the phage may allow the identification of unique peptide motifs with distinct binding characteristics. These peptide motifs could be used for the design of peptidomimetics with therapeutic applications if they inhibit the binding of B7-1 to its T cell receptors.
Mol Divers 1996 Feb
PMID:Utilization of multiple phage display libraries for the identification of dissimilar peptide motifs that bind to a B7-1 monoclonal antibody. 923 96

A selectivity of B7.1 (CD80) for promoting Th1 responses and B7.2 (CD86) for promoting Th2 responses in the murine system has recently been suggested. The present study explores this hypothesis, using human PBMCs and antigen-specific Th1 and Th2 clones. Proliferative responses of peripheral blood mononuclear cells (PBMCs) from ragweed-allergic, tetanus toxoid-immunized individuals were downregulated by treatment with anti-CD86 in ragweed- and tetanus toxoid-driven cultures (% Inhibition = 55 +/- 4 and 61 +/- 12, respectively; P < 0.03 relative to untreated cultures). Gene expression in PBMCs for interleukin (IL)-4, IL-5, and interferon gamma (IFNgamma), assessed by reverse-transcriptase polymerase chain reaction, was also downregulated by treatment with anti-CD86 in both the ragweed- and tetanus toxoid-driven systems. Neither independent efficacy nor synergy with anti-CD86 was apparent with anti-CD80 treatment; two different anti-CD80 blocking antibodies yielded identical results. Conversely, antigen-specific Th1 and Th2 clones were insensitive to treatment with either anti-CD80, anti-CD86, or a combination of the two. Unaffected parameters included proliferative response (P < 0.14 and 0.33, respectively, for Th1 and Th2), proinflammatory cytokine gene expression, and cytokine protein secretion into culture supernatants (P < 0.44 and 0.16, respectively, for IL-4 and IFNgamma). We conclude that CD86 is the primary B7 signaling homologue in human PBMC responses, and that second signal pathways through the B7 homologues have no effect on phenotypically differentiated T helper cells in humans.
Am J Respir Cell Mol Biol 1997 Aug
PMID:Differential regulation of human, antigen-specific Th1 and Th2 responses by the B-7 homologues, CD80 and CD86. 927 12

Human tumor cell lines derived from breast and ovarian carcinomas have been found to be ineffective in stimulating the induction phase of an immune response such as T cell proliferation in allogeneic mixed tumor cell lymphocyte cultures. Since representative tumor cell lines are effectively lysed by activated T lymphocytes, the induction of an effector phase is not impaired. In order to reconstitute the potential to induce primary T cell activation, we transfected CD80 into a breast (KS) and an ovarian carcinoma (GG) cell line. CD80 expression in KS cells resulted in improved primary T cell activation, whereas it was ineffective in the case of GG cells. However, treatment of CD80-transfected GG cells with INF-gamma rendered them immunogenic, and resulted in T cell proliferation. Likewise, TNF-alpha and/or INF-gamma augmented T cell proliferation induced by CD80-transfected KS cells. Furthermore, T lymphocytes stimulated with cytokine-treated CD80+ KS cells gave rise to a long term proliferating CD8+ CTL line with class I MHC restricted cytolytic antitumor activity. These studies emphasize the requirement for costimulation in generating tumor-specific immunity, and demonstrate the efficacy of CD80 in generating CD8+ cytolytic T lymphocytes.
Cytokines Mol Ther 1995 Sep
PMID:CD80-transfected human breast and ovarian tumor cell lines: improved immunogenicity and induction of cytolytic CD8+ T lymphocytes. 938 77


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