Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent work has indicated the significance of IL-4- and IL-5-secreting allergen-specific human Th2 lymphocytes in the control of immune responses to allergens in atopic individuals. The precise allergenic epitopes that activate these allergen-specific Th2 cells are, however, hardly known. We analyzed the epitope-specificity of T lymphocytes specific for Der p II, one of the major allergens of house dust mite Dermatophagoides pteronyssinus. Using a panel of overlapping synthetic peptides that span the entire Der p II molecule, we could demonstrate that polyclonal Der p II-specific T cell lines prepared from the peripheral blood of five atopic patients can react with at least 10 different epitopes of the molecule. Each donor showed a different pattern of reactivity with the synthetic peptides, suggesting that Der p II contains multiple T cell epitopes that may differ from individual to individual. We studied the specificity of the T cell response to Der p II in more detail in one atopic patient using a short term polyclonal T cell line that strongly reacted to one single peptide (116-129) of the allergen. From this patient we established a panel of 11 Der p II-specific TLC. Ten TLC were of the CD3+ CD4+ phenotype and showed a high IL-4/IFN-gamma production ratio, whereas another TLC expressed CD3 and CD8 and failed to secrete substantial IL-4 and IFN-gamma. The use of at least four different TCR V beta gene segments was shown within this panel TLC. All TLC tested recognized the allergen in an HLA-DR1-restricted manner. Although this patient reacted to only one peptide on the polyclonal level, two T cell epitopes were identified on the clonal level by using synthetic peptides and autologous APC to stimulate the TLC. Combining data of CD4/CD8 expression, TCR V beta usage, and epitope specificity, at least six different types of Der p II-specific TLC could be identified within this patient. Binding of IgE to all synthetic peptides of Der p II is low and of low affinity, which may be of particular importance with respect to possible desensitization protocols using such peptides.
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PMID:T cell epitopes of house dust mite major allergen Der p II. 768 99

This study demonstrates that a syngeneic specific cytotoxic T lymphocyte (CTL) response to a class I major histocompatibility complex (MHC) positive tumour requires dual processing and recognition of tumour antigens. One type of antigen is processed and expressed in association with class I MHC at the surface of intact tumour cells. It is recognized by CD8 alpha, beta TCR CTL in vitro and by protective immune T cells in vivo and thus functions as a tumour-associated transplantation antigen (TATA). The other type of antigen is processed and expressed by distinct host APC in association with class II MHC. This is recognized by immune CD4 T cells which function as essential helper cells in the generation of the CD8 CTL response. These conclusions are supported by cell depletion and reconstitution experiments as well as by blocking experiments with monoclonal antibodies using the highly metastatic class II negative murine lymphoma ESb as a model system. The existence of two types of cognate T cell responses in a syngeneic anti-tumour response was directly proved by the establishment of two types of tumour specific T cell lines which required as co-stimulator either MHC class II positive APC or IL-2. In suboptimal mixed lymphocyte tumour cell cultures either of these co-stimulator functions was found to be limiting the overall anti-tumour CTL response. The generation of the tumour specific CTL response could be blocked by monoclonal antibodies against all the molecules involved in the cognate interactions (i.e. class I MHC, CD8, class II MHC, CD4 and TCR) but not by anti-CD2 or anti-IgG. The strict requirement for helper cells and APC could be bypassed by the addition of recombinant IL-2 but optimal triggering of CD8 CTL-precursor required viable tumour stimulator cells. This well characterized in vitro assay may be useful (i) for monitoring the immune status of CD4 and CD8 immune T cells separately, for instance of tumour bearing and/or treated animals and (ii) for the development and testing of potent tumour cell vaccines with T cell stimulatory and/or co-stimulatory activities.
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PMID:Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. 790 Nov 50

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

The murine T cell surface molecules Ly-6C and Thy-1 are genetically and structurally distinct, yet they share two interesting properties: both are attached to the plasma membrane through a glycophosphatidylinositol linkage, and some mAb reactive with these molecules can activate T cells. Although mAb for Ly-6C and Thy-1 appear to mimic the function of physiologic ligands, direct evidence for the existence of these putative ligands has not been presented. In this report, we describe CTL clones that use Ly-6C and Thy-1 as accessory molecules for activation of cytolysis and the production of IFN-gamma based on inhibition of these functions with mAb. These studies were facilitated by the derivation of a nonactivating hamster IgM mAb specific for Ly-6C. CTL clones that use Ly-6C and Thy-1 as accessory molecules include a subpopulation of the previously described CD8+ alloreactive CTL that are not inhibited by mAb reactive with CD8, a CD8+ TCR-alpha/beta+ T cell clone specific for HSV glycoprotein D, and a CD4-CD8- TCR-gamma/delta+ T cell clone specific for HSV glycoprotein I. The role of Ly-6C and Thy-1 in target cell recognition is to some degree tissue-specific with respect to the APC/target cell. A mAb specific for Ly-6C appears to inhibit activation by prevention of adhesion between the effector cells and the target cells. This is the most direct evidence to date of a functional ligand for Ly-6C.
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PMID:Accessory molecules involved in antigen-mediated cytolysis and lymphokine production by cytotoxic T lymphocyte subsets. I. Identification of functions for the T cell surface molecules Ly-6C and Thy-1. 810 17

Primary CTL responses can be generated in vitro against defined peptides in association with class I MHC molecules. We show here that if cells obtained from a 5-day MLR are also included in the cultures, the response is greatly reduced if the added cells both carry CD8 and can bind the peptide. Our interpretation is that the added MLR cells are acting as deletional APC or veto cells. Peptide-specific CTL precursors recognize the peptide on the class I MHC of the CD8+ MLR cells and then receive a negative signal via CD8 on these cells. In support of this, when MLR cells carrying the Lyt-2.1 allele of CD8 were used to down-regulate the response of Ly-2.2+ responder cells, inclusion of anti-Ly-2.1 mAb in the cultures partially reversed the response reduction. Similar signaling may occur in vivo. When mice were injected i.v. with syngeneic lymphoid cells incubated with a peptide which they could bind, the response against that peptide was specifically reduced in a subsequent in vitro assay.
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PMID:Reduction of CTL antipeptide response mediated by CD8+ cells whose class I MHC can bind the peptide. 830 Nov 19

MRL/Mp-lpr/lpr (MRL/lpr) mice develop marked lymphadenopathy, characterized predominantly by Thy1+CD3+CD4-CD8- cells ("double negative T cells"; DNT). It is paradoxical that DNT proliferate poorly in vitro when stimulated through CD3 or by mitogens. The hamster mAb H1.2F3, raised against dendritic epidermal DNT, recognizes a very early activation (VEA) Ag, which is generally absent on resting cells but expressed soon after T cell activation with ConA or phorbol ester. Cross-linking of this disulfide-linked dimer in the presence of APC and phorbol ester induces proliferation of normal T cells. Therefore, we tested to see whether MRL/lpr DNT expressed this Ag and whether it might play a role in DNT expansion. Unmanipulated cells from enlarged MRL/lpr lymph nodes expressed VEA in an age-dependent manner, peaking at 3 to 4 mo of age. Only limited expression in a small subset of lymphocytes from the congenic MRL/Mp(-)+/+ strain was seen. VEA expression on freshly harvested MRL/lpr lymphocytes was seen mainly on DNT, yet double staining of the DNT for VEA Ag and three other markers known to be present on lpr DNT showed that the DNT were a heterogeneous population. In addition, some CD4+ T cells expressed VEA Ag. Despite their constitutive VEA Ag expression, MRL/lpr DNT showed no proliferative response to cross-linking with the H1.2F3 antibody. Furthermore, unlike normal T cells, they failed to respond to the antibody even when phorbol ester was added. The addition of supplementary cytokines did not correct this defect. These studies indicate that MRL/lpr DNT constitutively and aberrantly express VEA but do not respond when it is cross-linked. These abnormalities may result from the failure to express Fas, the recently reported apoptosis-inducing receptor defective in lpr mice.
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PMID:Aberrant expression of the very early activation antigen on MRL/Mp-lpr/lpr lymphocytes. 838 Apr 29

The initial event triggering the activation of Th cells occurs when the TCR interacts with antigenic peptide in the context of the MHC II on APC. Various T cell accessory molecules including CD4, CD28, and LFA-1 participate and facilitate the activation event. Although some evidence for the interaction of MHC II and CD4 is available, the site of MHC class II (alpha-chain, beta-chain, or both chains) for CD4 interaction has not yet been clearly defined. Results from different laboratories had indicated the involvement of alpha 1, beta 1, and beta 2 domains of MHC class II molecules in CD4 interaction. Recently, a conserved site of DR beta 2 domain has been identified that involves CD4 interaction that is analogous to MHC class I binding site for CD8 molecule. In this report, direct binding of affinity-purified HLA-DR2 dimer and its isolated alpha- and beta-chains to CD4 was studied using a CD4-transfected HeLa cell line. Preferential binding of the beta-chain and intact MHC II dimer to the CD4-transfected cells was observed and found to be specifically inhibited by anti-CD4 mAb. In contrast, the isolated alpha-chain of HLA DR2 did not show significant binding to CD4-transfected cells. Complexes of radiolabeled DR2 dimer or beta-chain alone with an immunodominant epitope from myelin basic protein (83-102) did not show any further increase in binding of these molecules. Binding of the beta-chain to CD4+ cells was markedly inhibited by a DR beta 1 peptide (35-46) and was partially inhibited by a DR beta 2 peptide (134-148) of MHC class II molecule. These results suggest the involvement of at least two conserved regions of the beta polypeptide chain of MHC class II in CD4 interaction. Because in our experiments transfected cells lack TCR molecules and the binding of DR2 to the CD4-transfected cells was unaffected by added antigenic peptide, it is possible that the interaction of MHC class II to CD4 is independent of TCR occupancy.
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PMID:Purified beta-chain of MHC class II binds to CD4 molecules on transfected HeLa cells. 843 82

In this article we propose that anti-rejection immunotherapies for countering acute allograft rejection can be designed around manipulation of the cell surface phenotype of alloantigen-presenting cells (allo-APCs) in ways that convert them from T cell activators to inhibitors. It is further suggested that a class of molecules, termed "coinhibitors," can be defined that carry out this APC conversion process. Data are summarized indicating that the human lymphoid cell surface molecule CD8 has such a trans-coinhibitor function which is in addition to the cis-coreceptor and adhesin functions traditionally ascribed to it. Antisense and sense gene transfer studies indicate that CD8 on the surface of allo-APCs leads to inhibition of allospecific T cell responders. We have explored the possibility of using protein, rather than gene, transfer as a therapeutic strategy for delivering CD8 to APC surfaces. Two membrane-binding variants of CD8 have been assembled to show retention of the coinhibitor function of native CD8. Immunotherapeutic possibilities associated with these chimeric CD8 polypeptides in the clinical context of renal and other organ transplantation are considered.
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PMID:Prospects for anti-rejection therapies based upon CD8-dependent immunoregulation. 846 13

Dominant second signals for T cell activation can be generated through interactions between CD28 and CTLA-4 on T cells with their co-stimulatory ligands B7-1 and B7-2 on APC. Nevertheless, some B7-negative cell lines appear capable of providing second signals to T cells, illustrating that B7-independent co-stimulatory pathways may exist. One such cell line, the peptide-transporter defective T lymphoma RMA-S, was investigated in the present study, to determine the origin of the co-stimulatory effects it provides. RMA-S can support clonal expansion of purified CD4 or CD8 T cells from unprimed mice activated with concanavalin A (ConA) or immobilized anti-CD3. Nevertheless, RMA-S does not express B7-1 or B7-2, nor does it express other known co-stimulatory molecules, i.e. CD40, gp39, CD70 and HSA. Also, co-stimulation provided by RMA-S could not be blocked by antibodies or fusion proteins specific for these co-stimulatory molecules, excluding their participation. However, RMA-S' co-stimulatory activity is dependent on adhesive interactions. RMA-S is incapable of IL-2 production in the presence of ConA or anti-CD3, but T cells co-stimulated by RMA-S produce IL-2 and IFN-gamma upon anti-CD3- or ConA-induced activation. Furthermore, co-stimulation of antigen-specific T cell proliferation of both class I- and class II-restricted T cell clones can be provided by RMA-S, and RMA-S can preclude induction of anergy by 1-ethyl-3-(3-dimethyl amino propyl)carboiimide-fixed APC in a class II-restricted T cell clone. The results suggest that potent co-stimulatory pathways can be induced by cellular interactions between a T lymphoma, RMA-S and T cells, not involving gp39, CD40, CD70, HSA, B7-1 (CD80) or B7-2 (CD86). Characterization of the molecules involved is in progress.
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PMID:A T cell lymphoma can provide potent co-stimulatory effects to T cells that are not mediated by B7-1, B7-2, CD40, HSA or CD70. 858 81

Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.
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PMID:T cell suppression in transplantation tolerance through linked recognition. 862 93


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