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)

Exogenous Ag in the extracellular fluids do not gain access to the class I Ag-presenting pathway in most cells. However, there is an APC resident in spleen that can process and present exogenous Ag in association with class I molecules. We characterize the phenotype of this cell. This APC is of low buoyant density, is adherent to Sepharose and glass, and expresses both class II molecules and FcR. This phenotype identifies this APC as a macrophage. Resident, peptone- and thioglycolate-induced peritoneal macrophages also display this Ag-presenting activity. Analysis with CTL clones suggest that this Ag-presenting pathway may be active in only a subset of macrophages. A similar Ag-presenting activity is also present in dendritic cell-enriched populations from spleen although we cannot rule out the possible involvement of contaminating macrophages. In contrast, B and T cells that are resident in spleen and LPS blasts are unable to present exogenous Ag in association with class I molecules. The presentation of exogenous OVA with class I molecules is not inhibited by the inhibitors of thiol proteases, leupeptin, and antipain. The presence of gelonin, a ribosomal inactivating protein, in the extracellular fluids inhibits the ability of these APC to present exogenous OVA. Under identical conditions, gelonin does not inhibit Con A-stimulated T cell proliferation, or LPS-stimulated B cell proliferation and Ag presentation. These results are discussed in relation to the potential pathways through which an Ag in the extracellular fluids is presented with MHC class I molecules.
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PMID:Characterization of antigen-presenting cells that present exogenous antigens in association with class I MHC molecules. 841 76

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

The work presented in this review suggests that in human and murine type I diabetes, defective MHC class I expression on APC is linked to autoimmunity. The defect in self-antigen presentation is present on prediabetic and diabetic APC, and this presumably delivers abnormal or lack of signals to T cells to allow self tolerance. Since most autoimmune diseases have strong genetic linkage to MHC class II region, our recent results additionally demonstrating low MHC class I expression on lymphoid cells in a diversity of autoimmune diseases (hypothyroidism, rheumatoid arthritis, lupus, etc.) suggest that this pathway of abnormal class I presentation of self epitopes may be important for tolerance to many tissue-specific antigens (40). Certainly, the unanswered genetic questions will address the role of the specific genes controlling self-antigen presentation through MHC class I followed by T-cell education to self.
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PMID:Mechanisms of autoimmunity in type I diabetes. 844 41

Although T lymphocytes are the ultimate effectors of pancreatic beta cell destruction in autoimmune insulin-dependent diabetes, previous work has established that beta cell autoreactive T cells are generated in nonobese diabetic (NOD) mice as a result of APC dysfunctions. To determine if APC dysfunctions could result from developmental defects, we analyzed if macrophages (M phi) develop normally from NOD bone marrow stimulated with CSF-1 in the presence and absence of IFN-gamma. Due to interactions between the diabetogenic H-2g7 haplotype and background modifiers, NOD bone marrow cells were found to proliferate poorly to CSF-1 stimulation. IFN-gamma aberrantly increased CSF-1-stimulated proliferation of H-2g7 expressing bone marrow cells, although decreasing proliferation of bone marrow cells expressing diabetes resistant MHC haplotypes. FACS analysis indicated the diminished sensitivity of NOD hematopoietic precursors to CSF-1 was associated with a quantitative inability to generate phenotypically mature M phi. In addition to developmental defects, NOD M phi were also found to be functionally defective. Total MHC class I expression was aberrantly down-regulated in a tissue specific fashion in IFN-gamma-treated M phi from NOD mice, whereas MHC class I expression increased as expected in M phi from C57BL/KsJ (BKs) control mice. Total MHC class I expression also increased in IFN-gamma-treated M phi from NOR mice, a diabetes-resistant control strain that shares the H-2g7 haplotype of NOD, but contains BKs-derived genomic elements on chromosomes 2, 4, 11, and 12. This demonstrates differential trans-regulation of class I loci within the diabetogenic H-2g7 haplotype in NOD vs diabetes-resistant NOR mice. Aberrant down-regulation of MHC class I content in IFN-gamma-treated M phi from NOD mice was associated with decreased ability to activate CTL function. We propose these defects in M phi differentiation and function may interact with H-2g7 to generate APC in NOD mice that are unable to activate tolerogenic mechanisms, but remain capable of activating low level effector responses.
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PMID:Defects in the differentiation and function of antigen presenting cells in NOD/Lt mice. 845 Feb 29

Peptide fragments are displayed on the APC surface by MHC class I molecules as ligands for appropriate TCR. Sequence analysis of MHC-bound peptide mixtures has suggested that naturally processed peptides are defined by their length and by the presence of MHC allele-defined consensus motifs. To define the minimal OVA peptide presented by Kb MHC, and the requirements for generation of endogenous OVA/Kb complex, APC were transfected with OVA cDNA constructs. We show that optimal stimulation of OVA/Kb-specific B3Z T cell hybrid by Kb-APC requires the OVA257-264 peptide (SIINFEKL, SL8) whether added exogenously, or when synthesized endogenously as precursor polypeptides. Thus, all information necessary for expression of the OVA/Kb complex is contained within the Kb octapeptide motif shared by SL8. Unexpectedly, the SL8/Kb or the influenza NP/Db complexes were also generated in APC even when the peptide coding sequences were placed in incorrect translational reading frames. By contrast, identical manipulations of the translational reading frame of the lacZ reporter gene reduced protein synthesis to undetectable levels demonstrating the remarkable efficiency with which endogenous peptide/MHC are generated in and presented by APC to T cells. These characteristics of the endogenous presentation may explain how large numbers of distinct peptide/MHC complexes are displayed on the cell surface and surveyed by TCR.
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PMID:Endogenous generation and presentation of the ovalbumin peptide/Kb complex to T cells. 845 52

Treatment of RMA and EL4 cells or freshly isolated splenocytes with antisense (AS) oligonucleotides directed against the TAP-2 gene recreates the phenotype seen in cells that are genetically deficient in TAP function. Cells incubated with AS oligonucleotides exhibit reduced MHC class I expression on the cell surface, which can be increased by incubating the oligonucleotide-treated cells at 28 degrees C or by adding MHC haplotype-matched peptides to the culture medium. RMA cells or splenocytes treated with AS oligonucleotides and incubated with peptide were highly effective in generating primary CTL responses in vitro. The bulk of the AS oligonucleotide-responsive and CTL-inducing cells resided in the adherent fraction of splenocytes. Moreover, TAP-2 AS oligonucleotide-treated adherent splenocytes pulsed with OVA peptide elicited potent OVA-specific CTL responses in vivo and provided effective protection from challenge with tumor cells expressing the corresponding Ag. AS oligonucleotide technology provides a simple approach to develop broadly applicable methods for generating potent APC to study TAP function in normal cells and to identify other gene products involved in MHC class I presentation.
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PMID:Cells treated with TAP-2 antisense oligonucleotides are potent antigen-presenting cells in vitro and in vivo. 859 26

Positive selection of T lymphocytes expressing self. MHC-restricted T cell receptors is mediated by MHC molecules expressed on thymic stroma. Among the more controversial aspects of this process is the relative role of MHC molecules on epithelial versus bone marrow-derived stromal elements (BM-APC). For CD4+ T cells, the weight of evidence suggests that positive selection is driven solely by MHC class II molecules expressed on thymic epithelial cells. In contrast, recent experiments have been interpreted to show that CD8+ T cell development can be driven by MHC class I molecules expressed on BM-APCs as well as epithelial cells. To directly address this issue, we have examined the development of T cells expressing a transgenic, MHC class I-restricted TCR in mice deficient in the rearrangement of endogenous TCR genes. Since the transgenic TCR is the only TCR expressed, this system is extremely sensitive and specific for detecting even inefficient events in T cell development. Our experiments demonstrate that MHC class I expression exclusively on BM-APC is incapable of driving positive selection of CD8+ T cells. This finding, together with earlier experiments for MHC class II, suggests a qualitatively unique function of thymic epithelial cells in mediating positive selection.
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PMID:Can bone marrow-derived thymic stromal cells mediate the positive selection of class I-restricted T cells? 866 Aug 40

Immunomodulatory cytokines have been used with success as adjunctive therapy in genetic disorders such as chronic granulomatous disease and infectious diseases such as leishmaniasis and leprosy. As the first step toward developing novel methods to deliver immunomodulatory cytokines, we used retrovirus-mediated somatic gene transfer techniques to produce IFN-gamma from human peripheral blood CD34+ hemopoietic progenitor (PBHP) cells. After transduction, the PBHP cells were made to differentiate toward myelo-monocytic lineages. Only the PBHP-derived myelo-monocytic cells that were transduced with the IFN-gamma cDNA produced IFN-gamma(4 +/- 1.3 ng of IFN-gamma/10(6) PBHP cells.) Despite a reduction in the proliferation of IFN-gamma-transduced PBHP cells as well as a decrease in erythroid colony formation, there was an enhancement of monocyte differentiation and activation. Monocytes differentiated from the IFN-gamma-transduced PBHP cells demonstrated 1) up-regulation of MHC class I and II Ag expression, 2) increased Fc(gamma)RI expression, and 3) enhanced superoxide production in response to both opsonized zymosan (25-fold) and phorbol ester (3-fold). Furthermore, a functional response to a monocyte-specific chemokine, monocyte chemotactic protein-1 (mobilization of intracellular Ca2+) was seen only in the IFN-gamma-transduced cells. Thus, PBHP cells transduced with IFN-gamma cDNA produce not only biologically active IFN-gamma, but also enhanced monocyte differentiation, resulting in an activated state that includes unique functions, such as responsiveness to monocyte chemotactic protein-1. These transduced activated monocytes may be specifically suited to cellular therapy requiring homing to sites of inflammation where their anti- microbicidal, cytotoxic and APC functions play an important role in host defense against foreign pathogens.
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PMID:Autocrine activation of hemopoietic progenitor-derived myelo-monocytic cells by IFN-gamma gene transfer. 866 6

Proteolysis of endogenously synthesized cellular proteins is essential for constitutive display of processed peptide/MHC class I complexes on the APC surface for stimulating CD8+ T cells. However, the extent to which normal protein turnover serves as the source of processed peptides is not clear. To address this question, we used pairs of novel N-end rule substrates that varied in their intracellular stability and served as precursors for generating peptide/MHC class I (OVA257-264/Kb or influenza nucleoprotein 366-374/Db) complexes. Surprisingly, although each of three precursor pairs tested varied profoundly in their intracellular stability, they were indistinguishable in either T cell stimulation assays, or in the amounts of naturally processed peptides in the APC extracts. Our findings demonstrate that the proteolytic turnover of endogenously synthesized proteins is not directly proportional to the generation of processed antigenic peptide/MHC class I complexes.
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PMID:Generation of naturally processed peptide/MHC class I complexes is independent of the stability of endogenously synthesized precursors. 875 7

Regulatory T cells recognizing TCR determinants presumably play a critical role in the control of experimental autoimmune encephalomyelitis, a prototype tissue-specific autoimmune disease. This study was initiated to determine whether regulatory T cells can be induced against a V beta 17a CDR2 peptide (residues 50-68) in SJL/J mice. Although the TCR peptide showed regulatory effects in vivo, the presence of T cells specific for the peptide could not be proven with conventional proliferation assays. Unexpectedly, in the presence of myelin basic protein-specific T clone cells (Tcc), the sensitized spleen cells vigorously proliferated in response to the TCR peptide. The subsequent experiment showed that this was due to the outstanding capability of the Tcc as APC for the exogenous TCR peptide. Using the Tcc as APC, we were able to establish V beta 17a50-68-specific T cell lines from in vivo primed spleen cells. The line cells were MHC class I restricted and dominated by T cells with a distinct surface phenotype (CD4-CD8-V beta 17a+). Presentation of the peptide by the Tcc was inhibited by treatment with gelonin that could block a MHC class I presentation pathway. The ability of T cells to present the TCR peptide was not related to their Ag specificity, but correlated with the expression levels of MHC class I molecules and adhesion molecules such as intercellular adhesion molecule-1 and B7-1 on their surface. The TCR peptide-specific T cells produced a soluble mediator(s) that is inhibitory for T cell activation and were protective against actively induced experimental autoimmune encephalomyelitis. These results show that V beta 17a50-68 vaccination induces regulatory CD4-CD8- T cells that could interact with T cells presenting relevant TCR fragments.
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PMID:T-T cellular interaction between CD4-CD8- regulatory T cells and T cell clones presenting TCR peptide. Its implication for TCR vaccination against experimental autoimmune encephalomyelitis. 875 68


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