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)

It is now well established that CD4+ T cells can express cytotoxic activity. This type of cell-mediated cytotoxicity is associated with the Th1-, but not with the Th2-phenotype. While the activation of CD4+ CTL is MHC class II-restricted, the effector phase, i.e. the target cell killing is unrestricted and antigen non-specific. In analogy to CD8+ CTL, CD4-mediated target cell death is by DNA fragmentation. However, the molecular mechanism of killing differs from CD8-mediated lysis. Thus, CD4+ CTL preferentially lyse their targets via Fas-Fas ligand interaction, whereas the major cytotoxic effect of CD8+ CTL is by granule exocytosis, i.e. perforin and granzymes. Although CD8+ CTL can also express the FasL, their lytic activity through interaction with Fas is of less importance. Likewise, some CD4+ CTL may also kill by perforin/granzymes activity, but this pathway is of minor significance. The aims of CD8- or CD4-mediated lysis are also different. Thus, the major task of CD8+ CTL which recognize and kill their targets in the context of MHC class I molecules, is the lysis of virally infected cells and battling against tumor cells. CD4+ CTL, on the other hand, have an immunomodulatory role. Thus, they preferentially eliminate activated MHC class II-positive cells, i.e. APC, be they monocytes/macrophages, B cells or T cells. They may lyse these cells in order to prevent an overreaction of the ongoing immune response or in order to remove potentially hazardous cells upon completion of the immune response. The Fas-FasL pathway is particularly suitable for this task as myeloid or lymphoid cells express Fas only if activated, while FasL is preferentially expressed on activated CD4+ Th1 cells. Moreover, activated T cells eliminate themselves by the Fas-mediated pathway. Whether this happens by fratricide only, or also by suicide or both is open. Moreover, CD4+ CTL are particularly suitable for killing tumor cells as well, as they are efficient effectors in bystander lysis in contrast to CD8+ CTL. On the other hand, the non-specific killing via Fas-FasL interaction, which is an important reason for the bystander lysis, may have unwanted effects in that cells which should not be eliminated could be killed. Such reactions affecting various organs and cells, e.g. the liver, thyroid or islet cells of the pancreas could be an explanation for certain autoimmune diseases.
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PMID:Mechanism and biological significance of CD4-mediated cytotoxicity. 749 61

Induction of anergy and deletion due to apoptosis are two of the mechanisms involved in peripheral tolerance. To clarify the relationship between these two phenomena we have used an in vitro system of T cell Ag presentation. The recognition of Ag displayed by MHC class II-expressing T cells (T-APC) induces partial signals in Ag-specific T cell clones. This leads to a blunted intracellular calcium flux, and the T cells become unable to proliferate in response to further challenge with professional APC. These T cells are unable to produce IL-2, but retain the ability to release IL-4. In the present study, we report that for some T cell clones, the predominant outcome of Ag recognition on T cells is cell death. For susceptible T cell clones, the number of cells that die is proportional to the peptide concentration. This cell death resulted from Fas/Apo-1 (CD95)/Fas-ligand interactions between the T cells, in that Fas ligand expression was detected following overnight culture of T cells with T-APC and neutralizing anti-CD95 Ab protected from death. Most notably, following anti-CD95-mediated protection from apoptosis, the rescued T cells remained unable to respond to rechallenge with Ag-pulsed, professional APC. These data suggest that anergy and apoptosis can be separated as consequences of partial T cell signaling.
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PMID:Dissociation of T cell anergy from apoptosis by blockade of Fas/Apo-1 (CD95) signaling. 912 Feb 62

CD4+ and CD8+ T cells emerge from thymic selection expressing a TCR restricted by MHC class II (TCRII) and MHC class I (TCRI), and upon Ag stimulation develop respectively into Th and CTL effector cells. The influence of thymic differentiation and antigenic stimulation on the determination of T cell functions was studied, with CD4+ T cells expressing a transgenic TCRI that reacts with the class I alloantigen H-2K(b) in a CD8-independent fashion. Such T cells additionally express a TCR, probably TCRII, in which the transgenic TCR beta-chain is associated with endogenously rearranged TCR alpha-chains. Upon in vitro stimulation with H-2K(b)-expressing cells, both CD8+ and CD4+ transgenic TCR+ T cells developed into CTL capable of killing Ag-expressing target cells through a perforin-dependent mechanism, and secreted IL-2 and IFN-gamma. Fas ligand-dependent killing could also be induced in both CD8+ and CD4+ in vitro stimulated T cells. The capacity to secrete IL-4 was restricted to the CD4+ T cells, however, suggesting that both CD8/CD4-shared and CD4-unique programs can be elicited by stimulation of CD4 T cells through a TCRI. Acquisition of CTL function was also induced upon class II alloantigen stimulation through the endogenously rearranged TCRII, which represents a polyclonal set of TCRs. IL-2, IFN-gamma, and after restimulation, IL-4, were also produced. Thus: 1) events associated with intrathymic selection influence the gene program activated in response to the same TCRI/APC interaction; and 2) CD4+ T cells expressing a TCRI and a TCRII can activate the same gene program after engagement of either one of these TCRs.
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PMID:Class I- and class II-reactive TCRs coexpressed on CD4+ T cells both trigger CD4/CD8-shared and CD4-unique functions. 914 64

Immunoregulation of lymphocytes and macrophages in the peripheral immune system is achieved in part by activation-induced cell death. Members of the TNF receptor family including Fas (CD95) are involved in the regulation of activation-induced cell death. To determine whether activation-induced cell death plays a role in regulation of dendritic cells (DCs), we examined interactions between Ag-presenting murine DCs and Ag-specific Th1 CD4+ T cells. Whereas mature bone marrow- or spleen-derived DCs expressed high levels of Fas, these DCs were relatively insensitive to Fas-mediated killing by the agonist mAb, Jo-2, as well as authentic Fas ligand expressed on the CD4+ T cell line, A.E7. The insensitivity to Fas-mediated apoptosis was not affected by priming with IFN-gamma and/or TNF-alpha or by blocking the DC survival signals TNF-related activation-induced cytokine and CD40L. However, apoptosis could be induced with C2-ceramide, suggesting that signals proximal to the generation of ceramide might mediate resistance to Fas. Analysis of protein expression of several anti-apoptotic mediators revealed that expression of the intracellular inhibitor of apoptosis Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein was significantly higher in Fas-resistant DCs than in Fas-sensitive macrophages, suggesting a possible role for Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein in DC resistance to Fas-mediated apoptosis. Our results demonstrate that murine DCs differ significantly from other APC populations in susceptibility to Fas-mediated apoptosis during cognate presentation of Ag. Because DCs are most notable for initiation of an immune response, resistance to apoptosis may contribute to this function.
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PMID:Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. 1055 53

B cells can serve dual roles in modulating T cell immunity through their potent capacity to present Ag and induce regulatory tolerance. Although B cells are necessary components for the initiation of spontaneous T cell autoimmunity to beta cell Ags in nonobese diabetic (NOD) mice, the role of activated B cells in the autoimmune process is poorly understood. In this study, we show that LPS-activated B cells, but not control B cells, express Fas ligand and secrete TGF-beta. Coincubation of diabetogenic T cells with activated B cells in vitro leads to the apoptosis of both T and B lymphocytes. Transfusion of activated B cells, but not control B cells, into prediabetic NOD mice inhibited spontaneous Th1 autoimmunity, but did not promote Th2 responses to beta cell autoantigens. Furthermore, this treatment induced mononuclear cell apoptosis predominantly in the spleen and temporarily impaired the activity of APCs. Cotransfer of activated B cells with diabetogenic splenic T cells prevented the adoptive transfer of type I diabetes mellitus (T1DM) to NOD/scid mice. Importantly, whereas 90% of NOD mice treated with control B cells developed T1DM within 27 wk, <20% of the NOD mice treated with activated B cells became hyperglycemic up to 1 year of age. Our data suggest that activated B cells can down-regulate pathogenic Th1 immunity through triggering the apoptosis of Th1 cells and/or inhibition of APC activity by the secretion of TGF-beta. These findings provide new insights into T-B cell interactions and may aid in the design of new therapies for human T1DM.
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PMID:Lipopolysaccharide-activated B cells down-regulate Th1 immunity and prevent autoimmune diabetes in nonobese diabetic mice. 1144 Nov 19

The Tec family tyrosine kinase, IL-2-inducible T cell kinase (Itk), plays an important role in TCR signaling. Studies of T cells from Itk-deficient mice have demonstrated that Itk is critical for the activation of phospholipase-Cgamma1, leading to calcium mobilization in response to TCR stimulation. This biochemical defect results in reduced IL-2 production by Itk-deficient T cells. To further characterize the downstream effects of the Itk deficiency, we crossed Itk-/- mice to a TCR-transgenic line and examined T cell responses to stimulation by peptide plus APC. These studies show that Itk is required for maximal activation of early growth responses 2 and 3 and Fas ligand transcription after TCR stimulation. These transcriptional defects lead to reduced activation-induced cell death of stimulated Itk-/- T cells, both in vitro and in vivo. Together these studies define an important role for Itk in TCR signaling, leading to cytokine gene expression and activation-induced cell death.
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PMID:Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase. 1185 2

Collagen II (CII)-induced arthritis in DBA/1j mice is mediated by both CII-reactive T cells and anti-CII Ab-producing B cells. To determine the relative role of these processes in the development of arthritis, we specifically eliminated CII-reactive T cells by treating the mice with CII-pulsed syngeneic macrophages that had been transfected with a binary adenovirus system. These macrophages express murine Fas ligand in a doxycycline-inducible manner with autocrine suicide inhibited by concomitant expression of p35. The mice were treated i.v. with four doses of CII-APC-AdFasLp35Tet or a single dose of AdCMVsTACI (5 x 10(9) PFU), or both simultaneously, beginning 2 wk after priming with CII in CFA. Treatment with CII-APC-AdFasLp35Tet alone or in combination with a single dose of AdCMVsTACI prevented the development of CII-induced arthritis and T cell infiltration in the joint. The elimination of T cells was specific in that a normal T cell response was observed on stimulation with OVA after treatment with CII-APC-AdFasLp35Tet. Treatment with AdCMVsTACI alone prevented production of detectable levels of circulating anti-CII autoantibodies and reduced the severity of arthritis but did not prevent its development. These results indicate that the CII-reactive T cells play a crucial role in the development of CII-induced arthritis and that the anti-CII Abs act to enhance the development of CII-induced arthritis.
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PMID:Depletion of collagen II-reactive T cells and blocking of B cell activation prevents collagen II-induced arthritis in DBA/1j mice. 1193 77

In vivo administration of APC expressing Fas ligand (Fas-L(+) dendritic cells (DCs)) has shown promise in dampening allergic reactions and transplant rejection. Since the effect in these studies was mainly on CD4 lymphocytes, our goal was to evaluate the ability of such killer DCs to eliminate antiviral CD8 lymphocytes and in this way ameliorate viral immunopathology or, conversely, impede viral clearance. Intravenous administration of Fas-L(+) DCs resulted in a 50% reduction of lytic CD8 precursors following intracerebral infection with lymphocytic choriomeningitis virus (LCMV), and accordingly, immunopathology and survival of LCMV meningitis were improved, whereas viral clearance remained unaffected. In transfer studies the effect of the Fas-L(+) DCs was only quantifiable on experienced, not naive, CD8 lymphocytes. Importantly, loading of Fas-L(+) DCs with viral Ag before therapy was not necessary to achieve this effect, indicating that non-LCMV-infected Fas-L(+) DCs acquired viral Ag during acute LCMV infection in vivo. Our studies delineate important aspects for the clinical use of Fas-L(+) DCs in vivo. One should expect that they acquire viral Ags and suppress antiviral CD8 responses to some degree when given while an acute infection is ongoing. In terms of safety it is encouraging that resolution of the infection, at least in the case of LCMV, is not inhibited.
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PMID:Reduction of antiviral CD8 lymphocytes in vivo with dendritic cells expressing Fas ligand-increased survival of viral (lymphocytic choriomeningitis virus) central nervous system infection. 1239 Nov 97

In cancer, the coordinate engagement of professional APC and Ag-specific cell-mediated effector cells may be vital for the induction of effective antitumor responses. We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement combined with IL-2 administration to stimulate T cell expansion would act coordinately to enhance the adaptive immune response against cancer. In mice bearing orthotopic metastatic renal cell carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither agent administered alone, induced complete regression of metastatic tumor and specific immunity to subsequent rechallenge in the majority of treated mice. The combination of anti-CD40 and IL-2 resulted in significant increases in dendritic cell and CD8(+) T cell number in advanced tumor-bearing mice compared with either agent administered singly. The antitumor effects of anti-CD40 and IL-2 were found to be dependent on CD8(+) T cells, IFN-gamma, IL-12 p40, and Fas ligand. CD40 stimulation and IL-2 may therefore be of use to promote antitumor responses in advanced metastatic cancer.
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PMID:Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses. 1259 3

Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas(+) Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.
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PMID:Mature but not immature Fas ligand (CD95L)-transduced human monocyte-derived dendritic cells are protected from Fas-mediated apoptosis and can be used as killer APC. 1275 15


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