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)

Ag-presenting cells provide at least two distinct signals for T cell activation. T cell receptor-dependent stimulation is provided by presentation of a specific peptide Ag in association with MHC molecules. In addition, APC also supply costimulatory signals required for T cell activation that are neither Ag- nor MHC restricted. One such costimulatory signal is mediated via the interaction of B7 on APC with the CD28 receptor on T cells. Recently, CTLA-4 has been shown to be a second B7 receptor on T cells. In the present report, we have examined the expression of CD28 and CTLA-4 on a panel of resting and activated normal T cell subsets and T cell clones by RNA blot analysis in an attempt to determine whether their expression defines reciprocal or overlapping subsets. CD28 was detected in resting T cells, whereas CTLA-4 was not. After stimulation with PHA and PMA for 24 h, CTLA-4 mRNA was expressed in both the CD4+ and CD8+ subsets as well as in CD28+ T cells. We examined 37 human and six murine T cell clones that had been previously characterized for their cytokine production. After activation, CTLA-4 and CD28 mRNA were coexpressed in 36 of 37 human T cell clones and all six murine T cell clones. These included T cells of CD4+8-, CD4-8+, and CD4-8- phenotypes as well as clones with Th1 and Th2 cytokine profiles. In contrast, CD28 but not CTLA-4 mRNA was detected in leukemic T cell lines and myelomas. CTLA-4 and B7 mRNA but not CD28 mRNA was detected in two long term HTLV-I-transformed T cell lines. These data demonstrate that CD28 and CTLA-4 mRNA are coexpressed in most activated T cells and T cell clones, providing evidence that they do not define reciprocal subsets. Moreover, they are consistent with the hypothesis that B7 transmits its signal through a single receptor, CD28, on resting T cells, and multiple receptors, CD28 and CTLA-4, on activated T cells.
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PMID:CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production. 128 Nov 86

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

Since mouse keratinocytes are tolerogenic antigen presenting cells for T cell activation, the expression of second signal molecules such as B7-1 was targeted to epidermal keratinocytes (KC) in vivo in transgenic mice. The expression vector used to create transgenic mice consisted of a keratin 14 promoter fused 5' to the full length open reading frame of the cDNA encoding mouse B7-1 (between 10 and 30 copies of the transgene per genome). Expression of B7-1 cell surface protein was assessed by in situ immunostaining of cryostat sections of tail skin with CTLA-4/Ig fusion protein, revealing high levels of cell surface expression of B7 by all epidermal KC of transgenic mice, and a lack of such expression in nontransgenic animals. The skin of such transgenic mice (derived from three different founder mice) was grossly and histologically normal, with normal numbers of Langerhans cells and dendritic epidermal T cells. Immunologic challenge of transgenic mice with epicutaneous haptens such as fluorescein isothiocyanate revealed enhanced and persistent delayed-type hypersensitivity responses, with an altered kinetics of resolution when compared with nontransgenic controls. These data indicate that in normal, nontransgenic mice, tolerogenic antigen presentation by KC plays an important physiologic role in damping T cell-mediated inflammation in the skin by competing with professional APC for TCR occupancy in antigen specific T-lymphocytes that migrate into the epidermis. This also implies that altered regulation of B7-1 gene expression by epidermal cells may account for skin "hyperresponsiveness" encountered in some chronic dermatologic disorders.
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PMID:Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen. 751 45

Signals initiated through both the TCR complex and CD28 are required for optimal activation of T lymphocytes. Recently, it has been demonstrated that CD28 interacts with two different ligands, designated CD80 (B7/B7-1) and CD86 (B70/B7-2). We have produced stable transfectants that express CD80, CD86, or both ligands and have examined their ability to costimulate T cell proliferation, cytokine production, and the generation of CTL. When we used small, resting human peripheral blood T cells as responders, both CD80 and CD86 transfectants efficiently costimulated anti-CD3 mAb-induced proliferation and the secretion of IL-2 and IFN-gamma. Additionally, both CD80 and CD86 transfectants were able to generate functional CTL. The magnitude and kinetics of these responses were similar, which indicates that both ligands provide efficient costimulatory signals. Because many APCs coexpress both CD80 and CD86, we compared the ability of anti-CD80 and anti-CD86 mAbs to inhibit allogeneic MLR stimulated with B lymphoblastoid cell lines and showed that it is necessary to inhibit interactions with both ligands to optimally block CD28-dependent proliferation. Given the limited homology of CD80 and CD86, it was surprising that the binding of CD28-Ig fusion protein to CD80 and that to CD86 transfectants were essentially indistinguishable. Binding of CTLA-4-Ig fusion protein to both transfectants also was quite similar, but was of higher affinity than CD28-Ig binding. Results from these studies indicate that both CD80 and CD86 are potent and similar costimulators of T lymphocytes. Therefore, the role of CD80 and CD86 in an immune response may be determined primarily by their differential expression on APC.
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PMID:CD80 (B7) and CD86 (B70) provide similar costimulatory signals for T cell proliferation, cytokine production, and generation of CTL. 752 24

Dendritic cells (DC) are potent APCs, able to induce efficiently primary T cell-mediated responses to foreign Ags. To assess the efficiency of DC, as compared with other APC types, in the in vivo presentation of self-Ags to CD4+ T cells, we analyzed processing and presentation to class II-restricted T cells of endogenous naturally processed self-epitopes constitutively expressed by mouse APC. Mouse beta 2-microglobulin (m beta 2-m) peptides corresponding to residues 26-39 and 24-36 are constitutively presented, in mice expressing m beta 2-m, by I-Ad and I-Ed molecules respectively, as demonstrated by activation of m beta 2-m-specific T cell hybridomas generated in BALB/c beta 2-m-deficient mice. These dominant, naturally processed self-epitopes of m beta 2-m are presented by APC from a variety of tissues, including the thymus. To analyze the relative efficiency of different APC populations in the presentation of self-beta 2-m, the ability of purified DC, macrophages, and large or small B cells to stimulate m beta 2-m-specific T cell hybridomas was tested. Naturally processed self-m beta 2-m epitopes are constitutively presented to T cells by any class II-positive APC tested, but with highest efficiency by splenic and thymic DC, followed by macrophages, large B cells, and small B cells. This hierarchy of self-beta 2-m presentation does not depend on differential processing capacity of these APC populations, and it correlates with expression of CTLA-4 ligands and ICAM-1 molecules, rather than with expression of class II molecules.
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PMID:Dendritic cells are the most efficient in presenting endogenous naturally processed self-epitopes to class II-restricted T cells. 752 78

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

Engagement of the TCR/CD3 complex together with ligation of CD28 by its counterstructures B7-1 (CD80) and B7-2 (CD86) on APC are required for mitogenic T cell activation. After activation, T cells not only express B7-1 and B7-2 molecules, but a second receptor for the B7 ligands, CTLA-4, can be found on their surfaces. We here show that B cells can be induced to express CTLA-4 on the plasma membrane. Similar to what has been reported for T cells, CTLA-4 expression on B cells was transient. Purified B cells did not express CTLA-4 when mitogenically activated with alpha IgM and CD40 Ab, but did express the molecule when cultured in the presence of membranes from activated T cells, which suggests that induction of CTLA-4 expression on B cells was dependent on direct cell-cell contact of B lymphocytes and activated T cells. CTLA-4 molecules isolated from either T or B cells were biochemically indistinguishable. Moreover, because the ability of chimeric B7-1/Ig proteins to bind to activated B cells was correlated with CTLA-4 expression levels on these cells, we conclude that B cell-expressed CTLA-4 has ligand binding capacity. These data suggest that costimulatory receptors and their specific ligands not only play a role in T cell stimulation, but contribute in a direct fashion to the regulation of B cell responses.
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PMID:Activated T cells can induce high levels of CTLA-4 expression on B cells. 754 32

In previous studies, we have shown that ultraviolet (UV) B radiation perturbs the APC function of Langerhans cells (LC) by interfering with as-yet unidentified co-stimulatory signals. Recently, B7.1 and B7.2 on APC were shown to deliver important co-stimulatory signals through interaction with their counter receptors CD28 and CTLA-4 on T cells. To determine whether UVB affects the functional expression of B7.1 or B7.2 on LC, B7.1 and B7.2 expression was studied on human LC by multiparameter flow cytometry. Little, if any, B7.1 or B7.2 was detected on LC freshly isolated from skin. However, following 48 h of tissue culture, expression of both B7.1 and B7.2 were markedly up-regulated. To test whether these molecules were functional, primary mixed epidermal cell leukocyte reactions (MECLR) were performed. Blocking monoclonal antibody (mAb) to B7.1 or B7.2 both inhibited the MECLR, with anti-B7.2 being much more effective than anti-B7.1. UVB radiation dose-dependently (100-200 J/m2) suppressed the culture-induced up-regulation of B7.1 and B7.2 on LC. Since LC exposed to the same UVB flux (UVB-LC) failed to stimulate alloreactive T cells in a MECLR, we questioned whether this was related to their inability to provide B7 co-stimulation. Indeed, when effective B7-CD28 signaling was ascertained by adding submitogenic doses of exogenous anti-CD28 mAb to UVB-LC, the proliferative response of alloreactive T cells was restored. We conclude that the suppressive effects of low-dose UVB radiation on the APC function of LC are, at least in part, due to an inhibition of functional B7.1 and B7.2 expression.
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PMID:Low-dose UVB radiation perturbs the functional expression of B7.1 and B7.2 co-stimulatory molecules on human Langerhans cells. 758 83

Staphylococcal enterotoxins, also known as superantigens (SAg), bind class II MHC molecules on APC and upon direct cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. The T cell surface molecule CD28 binds its costimulatory counter-receptor, B7 expressed on APC, and augments IL-2 production and T cell growth. Although the role of B7 costimulation during Ag-specific responses of T cells is established, its involvement during the activation of T cells with SAg has not been examined. Using a soluble Ig C gamma 1 chimera of CTLA-4, a second receptor for B7 and a homologue of CD28, this study examines the role of B7 expressed on APC during the induction of proliferation of CD4+ T cells upon stimulation with SAg (SAg/staphylococcal enterotoxins). CTLA-4lg, which has a higher avidity for B7 than CD28, had no effect on the synthesis of IL-2 as well as proliferative responses of CD4+ T cells induced by SAg presented on allogeneic EBV-transformed B cells, and IFN-gamma-activated endothelial cells. In contrast, T cell proliferation induced by alloAg presentation by the same APC was significantly inhibited by CTLA-4lg. mAb directed at the CD11a/CD18 molecule inhibited both SAg-induced and alloAg-induced proliferation of T cells. AlloAg-primed CD4+ T cells, which expressed both class II MHC and intercellular adhesion molecule-1 but not B7, presented SAg to and induced proliferation of both resting and SAg-primed T cells. These responses were inhibited by mAb directed at CD11a/CD18 but not by CTLA-4 Rg. These results suggest that SAg-induced responses differ from those induced by alloAg in that they are not obligatorily dependent on the costimulation by B7. In contrast, adhesive interaction between CD11a/CD18 on T cells and its counter-receptor on SAg-presenting cells is necessary and probably sufficient to support SAg-induced proliferation of T cells.
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PMID:Proliferation of human T lymphocytes induced with superantigens is not dependent on costimulation by the CD28 counter-receptor B7. 767 19

The B7 molecule is expressed by APC that can costimulate T cells by binding the T cell surface receptors CD28 and CTLA-4. The human epidermal Langerhans cell (LC) is one of the most potent APC, yet B7 expression by this cell type has not previously been assessed. We used a CTLA4-Ig fusion protein that binds B7 with high avidity to probe cell surface expression of B7 by cultured and noncultured LC. LC cultured for 1 or more days were specifically stained with biotinylated CTLA4-Ig and fluorescent streptavidin. In contrast, binding of CTLA4-Ig to freshly isolated LC was not detected. The cell surface distributions of B7 and of HLA-DR on cultured LC differed, as CTLA4-Ig binding was localized to discrete foci, whereas anti-DR mAb uniformly stained the LC plasma membrane. Analyses of epidermal cell (EC) mRNA indicated that the B7 gene is expressed by these cells. Thus, B7 gene probes specifically hybridized to polymerase chain reaction-amplified B7 mRNA isolated from cultured and noncultured EC. As LC are the only normal epidermal cell type that induces proliferation of allogeneic T cells, the role of B7 in this LC function was studied by coculturing highly purified resting CD4+ T cells and allogeneic EC in the presence of CTLA4-Ig, anti-CD54 (RR/1, anti-intercellular adhesion molecule-1) mAb, or both. CTLA4-Ig and RR/1 each inhibited CD4+ T cell responses to freshly isolated allogeneic EC, and cooperative inhibition of more than 90% was observed in cultures treated with both CTLA4-Ig and RR/1 at 5 micrograms/ml. CTLA4-Ig inhibited stimulation by either fresh EC or cultured EC, suggesting that the increased potency of cultured LC vs noncultured LC may reflect the time needed for noncultured LC to express cell surface B7 in vitro. These studies indicate that B7 is expressed on the cell surface of cultured LC, and that LC B7 costimulates the proliferation of resting allogeneic CD4+ T cells.
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PMID:Expression and function of B7 on human epidermal Langerhans cells. 767 25


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