Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed a panel of rat mAbs against dibutyryl cAMP-activated 5C2 cells. In this panel, one mAb, 1G10, recognized murine B7. Another mAb designated 2D10 did not bind to murine B7 but could recognize a surface molecule expressed only on dibutyryl cAMP-activated 5C2 mouse B lymphoma cells or on LPS-stimulated splenic B cells. This new molecule is referred to as early T cell costimulatory molecule-1 (ETC-1). From both activated 5C2 cells and splenic B cells, mAb 2D10 immunoprecipitated a 59- to 60-kDa protein, which was different from the 47- to 55-kDa murine B7 protein precipitated from the same cell populations. FACS analysis showed that, in contrast to B7, the expression of ETC-1 on 5C2 cells was induced by lower concentrations of dibutyryl cAMP and displayed a faster kinetics. LPS-stimulated splenic B cells expressed relatively low levels of B7 and much higher levels of ETC-1. Importantly, in an Ag presentation assay using activated 5C2 cells as APC, the secretion of IL-2 by C8A3 T hybrids was partially inhibited by mAb 2D10 alone and completely blocked by combination use of mAbs 2D10 and 1G10 in a dose-dependent and synergistic fashion. In a one-way primary MLR, mAb 2D10 alone at 0.1 to 1 microgram/ml inhibited T cell proliferation by 19 to 56%. However, an additive blocking effect (up to 76%) was observed when two mAbs were added in combination. Thus, our data have demonstrated that a novel T cell costimulatory molecule is present on activated murine B cells, which, in cooperation with B7, may play a critical role in optimal T cell activation.
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PMID:Monoclonal antibody 2D10 recognizes a novel T cell costimulatory molecule on activated murine B lymphocytes. 751 Jul 38

The interaction of T cell CD28/CTLA-4 receptors with B7-1 activation Ag on APC represents an important costimulatory pathway in T cell activation. However, it is now evident that this costimulatory pathway is neither unique nor universal for the activation of T cells. Our previous study indicated that a 60-kDa membrane protein, recognized by mAb 2D10, was expressed before B7 by activated murine B cells. This molecule was critically involved in activation of T cells in response to auto- and alloantigens. In the present study, we report on the isolation of a cDNA for this early T cell costimulatory molecule (ETC-1). ETC-1, like B7-1, is a member of the Ig supergene family and is composed of 303 amino acids. Nucleic acid sequence comparison indicated that ETC-1 is identical to the B7-2 molecule. When expressed in Chinese hamster ovary cells, ETC-1 showed profound T cell costimulatory activity as demonstrated by its ability to enhance CD4 T cell proliferation in response to Con A or anti-CD3 stimulation. Furthermore, ETC-1 also bound to both CD28-Ig and CTLA4-Ig fusion proteins. These results strongly support the notion that the interaction of ETC-1/B7-2 with CD28 or CTLA-4 receptors represents an alternative T cell costimulatory pathway.
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PMID:Molecular cloning and expression of early T cell costimulatory molecule-1 and its characterization as B7-2 molecule. 751 26

Interactions between the costimulatory molecule B7 on APC and its counter-receptor CD28 on T lymphocytes play a key role in the induction of cell-mediated immune responses. We studied the role of costimulation of tumor-reactive T cells by B7 in the immune destruction of the K1735-M2 mouse melanoma into which the gene encoding the human melanoma-associated Ag, p97, had been transfected. Previous work has demonstrated that the p97 transfectant cl62 is immunogenic but still grows progressively in immunocompetent C3H/HeN mice and that adoptive transfer of p97-specific CD4+ T cells can induce the regression of small established cl62 tumors metastatic to the lungs. We have now shown that expression of B7 in cl62 after retroviral-mediated gene transfer eliminated its ability to grow in immunocompetent mice but not in T cell-deficient nude mice. Mice immunized with B7-transduced p97+ cells had an increased activity of both CD4+ T cells, which could proliferate in response to the p97 Ag, and CD8+ CTL, which could lyse a broad spectrum of cultured syngeneic p97+ and p97- tumor lines but not allogeneic tumor lines or syngeneic lymphoblasts. Both CD4+ and CD8+ T cell subsets were required for tumor rejection, and the depletion of CD4+ T cells in vivo decreased the tumoricidal activity of CD8+ CTL. Treatment of mice bearing an 8-day established s.c. cl62 melanoma by i.p. injection of B7+ cells from 2A, a highly immunogenic p97 transfectant, resulted in complete tumor regression and cure, injection of B7- 2A cells did not. The therapeutic effect was specific for the cl62 tumor. Our results demonstrate that costimulation by B7 can amplify both CD4+ and CD8+ T cell responses against small tumors toward therapeutic benefit.
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PMID:Costimulation of tumor-reactive CD4+ and CD8+ T lymphocytes by B7, a natural ligand for CD28, can be used to treat established mouse melanoma. 751 29

Efficient initiation of a CD4 T cell response requires both activation through the TCR and costimulation provided by molecules on APC with counterreceptors on the T cell. We investigated the relative contribution of the ICAM-1:LFA-1 and B7:CD28/CTLA-4 costimulatory pathways in naive T cell activation, using either anti-CD28 Ab or fibroblast cell lines transfected with I-Ek, which express either no costimulatory molecules, ICAM-1 alone, B7-1 alone, or ICAM-1 and B7-1 together. Peptide Ag or immobilized anti-CD3 was used to provide the TCR signal. CD4 T cells from mice transgenic for the V beta 3/V alpha 11 TCR, which recognize a peptide of pigeon cytochrome c complexed to I-Ek, were used as a source of naive T cells. Naive T cells stimulated with Ag or anti-CD3 responded well to high numbers of APC expressing either ICAM-1 alone or B7-1 alone. However, APC expressing both ICAM-1 and B7-1 were much better stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers, indicating a synergy between the two pathways. Stimulation provided by ICAM-1 could not be solely attributed to adhesive strengthening of other pathways, since costimulation was seen when immobilized anti-CD3 was used and when ICAM-1 only APC were added, indicating that ICAM-1 was in fact acting as a classic costimulatory molecule. Both the magnitude of the response and the amount of costimulation required for response were dependent on the intensity of TCR interaction. These results suggest that an efficient naive T cell response requires both a strong TCR signal and more than one costimulatory signal that will synergize with the TCR signal. This offers an explanation as to why APC such as dendritic cells and activated B cells, which express high levels of multiple costimulatory/adhesion molecules, are the only APC that elicit naive T cell responses.
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PMID:Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. 754 26

M12 B lymphomas expressing transfected Ak molecules with truncated cytoplasmic domains have a defect in Ag presentation to some autoreactive T cell hybrids. This defect in Ag presentation is corrected by pretreatment of the B cells with agents that elevate intracellular cAMP. Here we show that dibutyryl-cAMP treatment of M12 B lymphomas leads to cell surface expression of the costimulatory molecule B7. Furthermore, CTLA4Ig, a ligand for B7, inhibits activation of an accessory signal-dependent T hybrid. B7 is also inducible in M12 B lymphomas upon MHC-restricted interaction with T cells that can be activated by the APC, but not by T cells that fail to respond to truncated MHC-bearing M12 cells. Activation of the unresponsive T hybrids with immobilized anti-CD3 confers on them the ability to induce B7 in the APC. Direct engagement by immobilized antibodies of MHC class II on M12 B lymphomas did not induce B7 expression. Taken together, these results imply that during T-B interaction, initial T cell activation events lead to the ability of the T cell to induce costimulatory activity in the B cell, which in turn further activates the T cell. Activated T cell supernatants induced a small amount of B7 but were not nearly as effective as cAMP or as coincubation of T and B cells. These results suggest a role for T-B contact or localized cytokine secretion in the induction of B7 during T-B interaction.
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PMID:Induction of costimulatory molecule B7 in M12 B lymphomas by cAMP or MHC-restricted T cell interaction. 768 Jun 86

The possibility of inducing antigen-presenting capacity in cells normally lacking such capacity, currently represents a major goal in vaccine research. To address this issue we attempted to generate 'artificial' APC able to stimulate CD4+ T cell responses when tumor cells were infected with a single, recombinant, vaccinia virus (rVV) containing the two genes encoding murine MHC class II I-Ak and a third gene encoding the murine B7-1 (mB7-1) costimulatory molecule. To minimize the cytopathic effect and to improve safety, in view of possible in vivo applications, we made this rVV replication incompetent by Psoralen and long wave UV treatment. Tumor cells infected with rVV encoding I-Ak alone, pulsed with hen egg white lysozyme peptide (HEL46-61), induced IL-2 secretion by an antigen-specific T hybridoma. Tumor cells infected with the rVV encoding mB7-1 provided costimulation for activating resting CD4+ T cells in the presence of ConA. Tumor cells infected with the rVV encoding I-Ak and mB7-1, and pulsed with chicken ovotransferrin peptide (conalbumin133-145), induced a significantly higher response in a specific Th2 cell clone (D10.G4.1) as compared to cells infected with rVV encoding I-Ak molecules only. Thus, this replication incompetent rVV represents a safe, multiple gene, vector system able to confer in one single infection step effective APC capacity to non-professional APCs.
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PMID:Induction of antigen-presenting capacity in tumor cells upon infection with non-replicating recombinant vaccinia virus encoding murine MHC class II and costimulatory molecules. 900 58

Human peripheral blood contains a small subpopulation of immature dendritic cells (iDC) distinguished from circulating monocytes by their low expression of CD14. We utilized leukapheresis and countercurrent centrifugal elutriation to obtain myeloid origin mononuclear cell (MOMC) fractions of monocytes and iDC for study. These subpopulations were ultrastructurally and immunophenotypically similar before culture. After a 20- to 96-h culture either alone, with recombinant human granulocyte-monocyte CSF, or with endotoxin, greater up-regulation of costimulatory molecule expression was observed among iDC than among monocytes, and only iDC expressed the activation molecule CD83. Treatment with rhIL-4 caused many MOMC to develop morphologic properties of dendritic cells within 96 h, but costimulatory molecule up-regulation and CD14 down-regulation were heterogeneous, and CD83 expression was infrequent. In contrast, calcium ionophore (CI) treatment induced rapid and consistent effects in MOMC from both healthy volunteers and cancer patients, including down-regulated CD14 expression, acquisition of dendritic cell morphologic properties, up-regulated MHC and costimulatory molecule expression, and de novo CD83 expression. Many such effects occurred within 20 h of treatment. CI treatment activated purified CD14+ monocytes and also enhanced the spontaneous activation of purified CD14-/dim iDC in culture. Unfractionated MOMC, purified monocytes, and purified iDC displayed equivalently enhanced T cell-sensitizing efficiency following CI treatment. CD4+ T cell sensitization to keyhole limpet hemocyanin and CD8+ T cell sensitization to MART-1 melanoma-associated peptide were achieved in a single culture stimulation. Therefore, circulating monocytes and iDC can be induced by CI to manifest properties of activated DC, providing large numbers of efficient, nontransformed autologous APC for T cell sensitization strategies.
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PMID:Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells. 937 70

T cells play a central role in the initiation, maintenance, and regulation of the immune response. Effector responses of T cells are controlled by complex combinations of lymphokines and adhesion/costimulatory molecule signals. To isolate the effects of specific adhesion/costimulatory molecules and to define the minimal molecular requirements of naive CD8+ T cell activation, we have developed an APC-free system for stimulation of naive CD8+ T cells. In this report, we demonstrate that immobilized MHC class I-peptide complexes can activate naive CD8+ T cells from TCR transgenic mice at low cell densities. The CD8+ T cells were stimulated to proliferate and secrete IL-2 independently of the molecular interactions between CD28/B7.1-B7.2 or LFA-1/ICAM-1 surface receptors. Previous reports have shown that CD28 ligation is necessary for late T cell survival of APC-stimulated naive CD8+ T cells. Our data suggest that under certain specific conditions of high intensity T cell signaling, early activation and late cell proliferation can occur independently of APC-derived costimulatory signals.
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PMID:Purified MHC class I and peptide complexes activate naive CD8+ T cells independently of the CD28/B7 and LFA-1/ICAM-1 costimulatory interactions. 953 Dec 73

It is well known that interactions between accessory molecules on T cells and their ligands on APC play a key role in regulating T cell effector activity. The factors controlling the expression of these molecules are thus important determinants in the outcome of T cell activation. We have examined the expression of the murine ligand for CD27, a costimulatory molecule on T cells. Evidence is shown that CD27L is expressed at a low level on resting B cells but not on T cells, and that activation of B cells by culture with LPS or anti-IgM Ab increases the expression of CD27L. Interestingly, coligation of CD40 down-regulates CD27L on LPS-activated B cells but not on anti-Ig-activated cells. These findings suggest that costimulation via the CD27-CD27L pathway may be limited to interactions involving Ag-specific B cells, i.e., B cells specifically activated via their Ig receptors. In addition, testing a spectrum of different cytokines indicated that IL-4 and TGF, but not IL-2, IL-10, or IFN-gamma, prevented up-regulation of CD27L expression on activated B cells even when activation was induced by Ig signaling. The capacity of IL-4 to prevent CD27L expression could thus serve to limit CD27-CD27L interactions to Th1-type T cell responses.
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PMID:CD40 and IL-4 regulate murine CD27L expression. 955 Mar 98

The requirement for T cell costimulation at sites of infection and inflammation is unresolved. Herpes stromal keratitis (HSK) is a CD4+ T cell-regulated inflammatory response to herpes simplex virus type 1 infection of the cornea. Our findings suggest that susceptibility to HSK is determined by the microenvironment of the infected cornea. The cornea is normally devoid of Langerhans cells (LC), but these APC are present in the surrounding conjunctiva, and migrate into the cornea following infection. The costimulatory molecule B7-2 was constitutively expressed on LC in conjunctiva, but B7-1 was not detectable until 3 days postinfection. LC were the only cells in the cornea that expressed B7-1 through 7 days postinfection. B7-1 was expressed on some, but not all, migrating LC, suggesting that LC migration and B7-1 expression can be independently regulated. The early LC migration and B7-1 expression was independent of T cells, but T cells were required for the massive accumulation of B7-1+ LC in the cornea at the onset of inflammation. Local inhibition of B7-1 function within the infected cornea prevented HSK. Locally blocking B7-2 function did not reduce HSK incidence, but markedly reduce HSK severity. This is the first direct demonstration that naturally expressed B7 is required within an inflammatory site.
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PMID:B7 costimulatory requirements of T cells at an inflammatory site. 959 Feb 54


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