Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.69 (APC)
16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of T cells often requires both activation signals delivered by ligation of the TCR and those resulting from costimulatory interactions between certain T cell surface accessory molecules and their respective counter-receptors on APC. CD11a/CD18 complex on T cells modulate the activation of T cells by interacting with its counter-receptors intracellular adhesion molecule (ICAM-1) (CD54) and/or ICAM-2 on the surface of APC. The costimulatory ability of ICAM-1 has been demonstrated. Using a soluble ICAM-2 Ig fusion protein (receptor globulin, Rg) we demonstrate the costimulatory effect of ICAM-2 during the activation of CD4+ T cells. When coimmobilized with anti-TCR-1 mAb ICAM-2 Rg induced vigorous proliferative response of CD4+ T cells. This costimulatory effect of ICAM-2 was dependent on its coimmobilization with mAb directed at the CD3/TCR complex but not those directed at CD2 or CD28. Both resting as well as Ag-primed CD4+ T cells responded to the costimulatory effects of ICAM-2. The addition of mAb directed at the CD11a or CD18 molecules almost completely inhibited the responses to ICAM-2 Rg. These results are consistent with the role of CD11a/CD18 complex as a receptor for ICAM-2 mediating its costimulatory effects. Stimulation of T cells with coimmobilized anti-TCR-1 and ICAM-2 resulted in the induction of IL-2R (CD25), and anti-Tac (CD25) mAb inhibited this response suggesting the contribution of endogenously synthesized IL-2 during this stimulation. These results demonstrate that like its homologue ICAM-1, ICAM-2 also exerts a strong costimulatory effect during the TCR-initiated activation of T cells. The costimulatory effects generated by the CD11a/CD18:ICAM-2 interaction may be critical during the initiation of T cell activation by ICAM-1low APC.
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PMID:Intercellular adhesion molecule-2, a second counter-receptor for CD11a/CD18 (leukocyte function-associated antigen-1), provides a costimulatory signal for T-cell receptor-initiated activation of human T cells. 134 50

Although ligation of the CD3/TCR complex initiates an activation signal in T cells, additional costimulatory signals generated during cell-to-cell interactions with APC transduced via ligation of CD11a/CD18 and CD28 by their specific counter-receptor intercellular adhesion molecule (ICAM)-1 and B7, respectively, are required for optimal T cell proliferation and cytokine synthesis. Using soluble IgC gamma 1 fusion proteins of these costimulatory counter-receptors, we have recently shown that unactivated resting CD4+ T cells and Ag-primed CD4+ T cells differ in their response to the costimulation by ICAM-1 and B7. Preferential proliferative responses of resting T and Ag-primed T cells to ICAM-1 and B7, respectively, prompted us to speculate that ICAM-1-induced signals may regulate coupling of the CD28 signaling pathway. Furthermore, both B7 and ICAM-1 are co-expressed on APC and thus, may co-regulate activation-driven maturation of T cells. In this study, we have examined regulatory effects of IgC gamma 1 fusion proteins of B7, ICAM-1, and ICAM-2 (a homologue of ICAM-1) on each other's costimulation. We first demonstrate that TCR-directed costimulation of resting CD4+ T cells with ICAM-1 (ICAM-1 priming) but not ICAM-2 induces increased responsiveness to B7. Priming of CD4+ T cells with ICAM-1 induced higher expression of both CD18 and CD28 than that with either B7 or ICAM-2. Cross-linking of CD28 induced faster and significantly higher cytoplasmic free calcium mobilization response in ICAM-1-primed CD4+ T cells than in resting, B7-primed, or ICAM-2-primed CD4+ T cells. B7 synergized with ICAM-1 but not ICAM-2 to augment proliferative responses of not only resting CD4+ T cells but also those that had been primed with either ICAM. Unlike resting or ICAM-2-primed CD4+ T cells, ICAM-1-primed CD4+ T cells efficiently proliferated in response to the synergistic costimulation of B7 and ICAM-2. In contrast, both ICAM-1 and ICAM-2 inhibit B7-driven proliferation of Ag-primed CD4+ T cells. Thus, B7 and ICAM-1 exert contrasting regulatory effects on the proliferation of CD4+ T cells depending on their state of activation-induced maturation.
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PMID:Differential regulatory effects of intercellular adhesion molecule-1 on costimulation by the CD28 counter-receptor B7. 138 17

We have investigated the role of CD2 molecules in Ag-specific T cell activation by using a mouse model system in which the function of CD2 can be analyzed without the apparent influence of major accessory molecules, such as CD4 or LFA-1. Transfection of the CD2 gene into a CD2- T cell hybridoma confers the enhancement of IL-2 production upon Ag stimulation. Anti-CD2 mAb inhibits the Ag-specific response of the CD2-transfectant, not only to the level of CD2- cells but to the background. B cells, but not MHC class II-transfected L cells, serve as APC to induce the inhibition of Ag response. The complete abrogation of the response is observed only upon the stimulation through TCR with Ag in the presence of APC but not through either TCR-CD3 or other molecules such as Thy-1. Furthermore, the inhibition can also be observed when anti-CD2 mAb is immobilized on culture plates, suggesting that the inhibition of Ag response results from transducing the negative signal through the CD2 molecule. The experiments on cytoplasmic domain-deleted CD2-transfected T cells reveal that the cytoplasmic portion is responsible for the CD2-mediated abrogation of Ag responses. These results imply that CD2 has important roles in T cell responses not only as an activation and adhesion molecule but also as a regulatory molecule of Ag-specific responses through the TCR.
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PMID:Induction of negative signal through CD2 during antigen-specific T cell activation. 168 Sep 13

We have concentrated here on the lymphokines which might serve to regulate the different pathways of precursor development. We suggest that, as a result of antigenic stimulation, specific precursor cells both proliferate and become committed to develop into either an effector cell, a memory cell or an anergized cell. Anergy has not been dealt with in this review, but it is likely to be one of the options available. The development of an effector population takes 4-7 d (quite analogous to the time it takes for CTLp to become CTL and for resting B to become Ab-forming cells). The effector populations are large, generally IL-2R-positive cells. These cells have upregulated many adhesion molecule systems [e.g., Pgp-1, LFA-1 and ICAM-1 (Swain unpublished)], but downregulated the Mel-14 homing receptor. Effectors are ready to respond to APC such as specific B cells with a rapid synthesis and secretion of lymphokines. The effector population is then quickly downregulated, both by the turn off of lymphokine synthesis/secretion and possibly by its own suicide. This kind of pattern makes teleological sense since the cells making such high titers of lymphokines could have many potent pleitropic effects. It also seems to be the strategy employed in the generation of other terminally differentiated effectors (such as CTL and plasma cells). The requirement for restimulation and the requirement for direct and perhaps prolonged contact between the helper effector and the APC-B cell can be expected to help ensure that these lymphokines are localized (reviewed in Swain & Dutton 1987, Swain & Croft 1990) and effectively delivered to specific responding cells. We postulate that at the same time, or perhaps subsequent to this, another set of signals drives precursors to generate prememory cells. Our studies suggest these emerging memory cells may be phenotypically unique and we postulate that they are specialized to become a "long-lived" population of memory cells that will persist indefinitely as a protective population of increased frequency for the antigen encountered and which is also able to respond more rapidly and effectively. The greater effectiveness of the memory response would thus be due to dramatically increased frequency, to characteristic and stable changes in adhesion molecule expression and to the fact that, in addition to IL-2, resting memory cells also secrete at least low titers of IL-3, IL-4, IFN-gamma and other lymphokines upon initial restimulation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. 168 76

T cell binding to target cells involves not only the TCR and its MHC-bound ligand, but also a collection of additional proteins on both the T cell and its target. In an attempt to identify new molecules involved in this binding, mAb were raised against APC, and screened for their abilities to inhibit T cell recognition of Ag plus MHC on B cells. Six antibodies were identified that inhibited this reaction and that bound a cell-surface glycoprotein (Lgp55), with core polypeptide Mr 30,000 and a glycosylated Mr of approximately 55,000 depending upon the cell source. The properties of Lgp55 were consistent with it being the mouse homologue of a recently identified human ligand (intercellular adhesion molecule-2) for lymphocyte functional Ag-1 because the proteins are of comparable Mr, and antibody to Lgp55, like anti-lymphocyte functional antigen-1, blocks T cell recognition of Ag presented by B cells, but not of Ag presented by mouse fibroblasts.
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PMID:Identification of a new cell surface glycoprotein with accessory function in murine T cell responses. 213 99

In vascularized organ transplantation, vascular endothelial cells (EC) confronting recipient T cells are potentially significant APC initiating cellular immune responses that lead to rejection. In the present study, we studied the ability of human EC to stimulate allogeneic T cells and the co-stimulatory molecules involved in this response. On both human umbilical vein endothelial cells (HUVEC) and microvascular endothelial cells (MVEC), MHC class I, intercellular adhesion molecule (ICAM)-1 and CD86 were constitutively expressed as assessed by flow cytometry. After IFN-gamma treatment, MHC class II expression was induced, and MHC class I and ICAM-1 were up-regulated. In contrast, the expression of CD86 was unchanged and CD80 was undetectable even after IFN-gamma treatment. Highly purified CD4+ T cells proliferated in response to IFN-gamma-treated allogeneic HUVEC and MVEC, and this response was efficiently blocked by mAb to MHC class II, ICAM-1 and CD86. Furthermore, the addition of anti-CD86 mAb to the primary culture with allogeneic EC resulted in the induction of alloantigen-specific anergy. These results suggest that CD86 expressed on EC plays a critical role in initiating cellular immune responses to vascularized allografts and would be an important target for immune intervention.
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PMID:CD86 (B70/B7-2) on endothelial cells co-stimulates allogeneic CD4+ T cells. 749 40

In a prospective, randomized, double-blind, placebo-controlled trial, rhSOD was given to cadaveric renal allograft recipients intravenously in a dose of 200 mg during surgery, and its effect on both acute and chronic rejection was investigated. The results showed that rhSOD exerts a beneficial effect on acute rejection episodes as indicated by a statistically significant reduction of first acute rejection episodes to 18.5% compared with 33.3% in controls, and a reduction in early irreversible acute rejection to 3.7% compared with 12.5% in controls. With regard to longterm results, there was a statistically significant improvement in the actual 5-year graft survival rate for rhSOD-treated patients to 68% (with a corresponding 13-year half-life) compared with 50% in controls (with a corresponding 6-year half-life). The incidence of acute rejection episodes did not prove to be a risk factor for long-term graft outcome. Rather only the combination of acute rejection episodes and the presence of uninfluenced reperfusion injury appeared to have a detrimental effect on long-term prognosis. The beneficial effect of rhSOD observed in this trial is not well understood, although one can assume that the effect is brought about by interference of rhSOD with ischemia or reperfusion injury to the allograft by oxygen-free radicals. In this sense, rhSOD may mitigate increased MHC expression and presentation, cytokine-adhesion molecule expression, and APC activation induced by reperfusion injury. In addition, in accordance with the "response-to-injury" hypothesis to explain the pathogenesis of arteriosclerosis, rhSOD may mitigate acceleration of chronic obliterative rejection or arterio-/arteriolosclerosis induced by reperfusion injury. In this sense, rhSOD may act indirectly by reducing acute rejection-mediated endothelial injury, or directly, by ablation of reperfusion-mediated acute endothelial injury.
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PMID:The impact of free radical-mediated reperfusion injury on acute and chronic rejection events following cadaveric renal transplantation. 791 55

We characterized the response of resting human CD8 T cells to allogeneic endothelial cells (EC). Both resting and IFN-gamma-pretreated EC stimulate similar CD8 T cell proliferative responses (peak, day 5 to 6), whereas only IFN-gamma-pretreated EC stimulate CD4 T cells. The response increases with increasing numbers of CD8 T cells from 25,000 to 400,000/well. The proliferation of CD8 T cells is inhibited by mAbs reactive with CD8 or HLA-A and -B molecules but not with CD4 or HLA-DR. mAb blocking studies show a role for CD2, LFA-3, and CD59, but not for intercellular adhesion molecule-1, intercellular adhesion molecule-2, very late activation Ag-4, vascular cell adhesion molecule-1, CD28, or CD28 ligand, as costimulatory molecules. The stimulation of resting CD8 T cells by EC causes secretion of IL-2 and IFN-gamma but not IL-4. Both proliferation and IFN-gamma secretion are inhibited by mAb to the IL-2R alpha subunit (CD25). Limiting dilution analysis suggests that approximately 1 in 20,000 resting CD8 T cells secrete IL-2 in response to allogeneic EC. EC stimulate greater than 1 in 10,000 CD8/CD45RO+ cells but fewer than 1 in 40,000 CD8/CD45RA+ cells, which indicates that primarily memory CD8 T cells respond to EC. Coculturing CD8 cells with EC stimulates a sufficient level of endothelial class II MHC expression to subsequently support a CD4 T cell proliferative response. The ability of memory CD8 T cells to proliferate against allogeneic EC, a nonclassical APC, and their ability to stimulate EC may contribute to the initiation of vascularized organ graft rejection.
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PMID:Antigen-presenting function of human endothelial cells. Direct activation of resting CD8 T cells. 798 46

It is now apparent that mAb to a growing number of intracellular adhesion molecules can not only promote allograft survival but also stimulate allogeneic tolerance in rodent transplant models. Intracellular adhesion molecules are responsible for a variety of immune functions, including proper lymphocyte migration and productive lymphocyte activation. Vascular endothelial cells have carefully regulated expression of adhesion molecules, which they use to control the homeostatic and inflammatory patterns of lymphocyte trafficking. This leads to the hypothesis that an impairment of lymphocyte trafficking by anti-adhesion molecules mAb results in prolonged allograft survival and/or allogeneic tolerance. In the broader view, endothelial cells belong to a small group of cell types that can serve as APC to T cells, and this APC function is strongly influenced by adhesion molecules. This leads to the hypothesis that an impairment of APC function by anti-adhesion molecule mAb results in allograft survival and allogeneic tolerance. The two hypotheses are not mutually exclusive, and both need to be tested. In general, however, it appears that intracellular adhesion molecules are intimately involved not only in the mechanisms of graft-induced alloactivation and but also in the mechanisms of allogeneic tolerance induction by virtue of their essential role in lymphocyte-endothelial and/or lymphocyte-APC interactions.
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PMID:Lymphocyte-endothelial interactions and tolerance induction. 801 35

In the complete absence of APCs staphylococcal superantigens induced IL-2, IL-4, IL-5, IFN-gamma, and IL-2R gene transcripts in both highly purified human T cells and FACs sorted CD4+ memory (CD45RA-) T cells. Secretion of IL-2, IL-4, and IFN-gamma, as well as DNA synthesis, on the other hand, required the presence of monocytes. At cytokine gene transcript level, three patterns of expression were noted after superantigen activation of T cells in the presence vs the absence of APC. mRNA levels for IL-2 were markedly up-regulated in the presence of monocytes, IL-4 and IFN-gamma transcripts increased only modestly, and IL-5 and IL-2R mRNA levels were unaffected. Blocking mAbs against LFA-1 and LFA-3 added to staphylococcal enterotoxin B (SEB)-activated cultures of T cells and autologous monocytes, reproducibly decreased both T cell proliferation and genetic expression of IL-2, IL-4, IL-5, and IL-2R, although having little or no effect on IFN-gamma transcripts. Further, under those conditions of blocking, secretion of IL-2 and IL-4 was dramatically decreased, whereas IFN-gamma secretion remained essentially unchanged. In contrast, LFA-1 and LFA-3 mAbs completely abrogated IFN-gamma secretion from PHA-activated T cell-monocyte mixtures, although having no inhibitory effect on T cell proliferation. These results indicate a characteristic and differential involvement of adhesion molecule-mediated signals in superantigen-induced T cell proliferation, differential cytokine gene expression, and cytokine secretion.
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PMID:IL-2, IL-4, and IFN-gamma gene expression versus secretion in superantigen-activated T cells. Distinct requirement for costimulatory signals through adhesion molecules. 812 Mar 74


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