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)

The identity and abundance of self-peptide/MHC class I complexes that serve as ligands for alloreactive T cells remain largely unknown. Using the Kb-restricted, alloreactive T cells as a probe, the Ag precursor gene, adenosine phosphoribosyl transferase (APRT), was isolated by expression cloning. Its naturally processed product was identified as the SLVELTSL (SEL8) octapeptide. The SEL8 peptide shared five residues with the previously identified SVVEFSSL (JAL8) peptide that stimulated the same T cell, but lacked the critical phenylalanine/tyrosine residue at the primary p5 anchor position. Despite the absence of this key conserved anchor residue, SEL8 was bound tightly by Kb MHC and yet was expressed at less than 10 copies/cell. Mutations in the donor APRT gene in the APC caused a concomitant loss in the ability of APCs to stimulate T cells. The results confirm that the display of peptide/MHC complexes in cells exceeds the predictions based upon consensus motifs, and that CD8+ alloreactive and conventional Ag-specific T cells are indistinguishable in their ability to recognize unique and rare peptide/MHC class I complexes.
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PMID:Alloreactive CD8+ T cells can recognize unusual, rare, and unique processed peptide/MHC complexes. 890 23

Cytotoxic T lymphocyte activation and most probably tolerance induction, is dependent on antigen presentation by a specialized group of cells, APC, including macrophages, dendritic cells and B cells. Since T lymphocytes are, at least, the majority of the time MHC molecule class-specific, CD8+ T cells require antigen presented by MHC class I molecules. MHC class I molecules are, however, restricted to presenting endogenously produced antigenic peptides. Most threats to the organism are of exogenous origin and do not uniformly affect all or even most of the cells of an organism. This precludes the likelihood that any number of APC would be involved in every threatening situation, which raises the important question of how T lymphocytes are indeed activated, especially CD8+ T cells (MHC class I restricted).
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PMID:Cellular immunity: the final paradigm? 904 39

Tumor cells genetically modified to coexpress certain cytokines (such as IL-7 or IL-4) and B7.1 have increased immunogenicity. Since tumor Ags can be presented either directly by tumor cells or indirectly by host APC (cross-priming), we asked whether B7.1 and IL-7 or IL-4 complemented each other by improving preferentially one or both pathways of Ag presentation. We used TS/A (H-2d) tumor cells and their IL-7, B7, and IL-7/B7 transfectants, and MCA205 (H-2b) tumor cells and their IL-4 and B7 transfectants. beta-galactosidase (beta-gal) was chosen as surrogate tumor Ag. beta-gal has different predominant MHC class I epitopes in H-2d and H-2b mice. Immunization of (H-2b x d)F1 mice with TS/A/beta-gal transfectants showed that both IL-7 and B7.1 and, as control, granulocyte-macrophage CSF augmented cross-priming and rejection of a challenge with MCA205/beta-gal (H-2b). Similarly, immunization with MCA205/beta-gal B7.1 or IL-4 transfectants enhanced cross-priming and rejection of a challenge with TS/A/beta-gal. beta-gal-specific rejection was confirmed by CTL assay. However, direct Ag presentation by tumor cells was enhanced only by B7.1, and not IL-7. For this study, H-2b nu/nu mice reconstituted with F1 lymphocytes were immunized with H-2d TS/A/beta-gal transfectants and challenged with TS/A/beta-gal. In conclusion, indirect Ag presentation was augmented by B7, IL-7, and IL-4, while direct Ag presentation was improved only by B7.
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PMID:Influence of gene-modified (IL-7, IL-4, and B7) tumor cell vaccines on tumor antigen presentation. 905 19

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

The mRNA and protein expression of the alpha- and beta-chains of IFN-gammaR were evaluated on a panel of human Th1 and Th2 clones. When cultured in IL-2-conditioned medium, both types of clones expressed mRNA for the alpha- and beta-chains, and both chains were present in the cytoplasm. Membrane expression of the alpha-chain was higher on Th2 than on Th1, whereas the beta-chain was poorly expressed on both types but increased following IL-2 withdrawal or PHA stimulation. In addition, both types of clones overexpressed MHC class I glycoproteins following IFN-gammaR triggering by exogenous IFN-gamma, although the kinetics was slower in Th1, and this exposure induced mRNA for IRF-1. When their TCR was triggered in the absence of APC, Th1 only underwent apoptosis. This activation-induced apoptosis was prevented by blocking of the alpha-chain or by IFN-gamma neutralization. Addition of IFN-gamma triggered the apoptosis of Th2 clones. Apoptosis of both types of clones was mediated by autocrine or exogenous IFN-gamma through the up-regulation of Fas-L expression, since anti-IFN-gammaR alpha mAb inhibited its expression on Th1 and exogenous IFN-gamma increased its expression on Th2. These results indicate that activated human Th1 and Th2 lymphocytes express IFN-gammaR alpha- and beta-chains and are both sensitive to signals provided by IFN-gamma. Data also suggest that IFN-gamma is critical for switching off their responses.
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PMID:Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones. 920 Apr 56

Dendritic cells (DC) play an essential role in the initiation of primary T cell responses to foreign Ag. It is likely that these potent APC are critical in the initiation of immune responses to pathogens, such as bacteria or parasites. However, little is known about the interaction of these important APC with pathogens. To address this issue, the interaction of the bacterium Mycobacterium tuberculosis with human DC was studied. DC generated from human peripheral blood by short term culture in medium containing recombinant human cytokines granulocyte-macrophage-CSF and IL-4 were capable of phagocytosing M. tuberculosis. Infection of DC with live M. tuberculosis bacilli resulted in increased APC surface expression of the costimulatory molecules CD54, CD40, and B7.1, as well as MHC class I molecules. In addition, infected DC secreted elevated levels of inflammatory cytokines, including TNF-alpha, IL-1, and IL-12. M. tuberculosis-infected human monocytes also secreted inflammatory cytokines, but exhibited no enhancement of costimulatory or MHC class I molecule expression. These data indicate that infection with M. tuberculosis results in the direct activation and maturation of these DC. In vivo, such activation may facilitate migration to the lymph nodes, and enhance presentation of Ag to T cells, thereby facilitating the induction of the immune response against this pathogen.
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PMID:Activation of human dendritic cells following infection with Mycobacterium tuberculosis. 921 78

A wide variety of human tumors express IL-10 for reasons poorly understood. We have analyzed the effect of spontaneous IL-10 expression by a mouse tumor (J558L) on its immunoparalyzing effect. Because "cross-priming" of T cells by host Ag-presenting cells for MHC class I-restricted tumor Ags is a major pathway for induction of tumor immunity and that is enhanced by granulocyte-macrophage (GM) CSF, we expressed this cytokine in J558L cells. GM-CSF-secreting cells were not effective when used for immunization against challenge with the parental tumor. Inhibition of IL-10 expression through an IL-10 antisense retrovirus restored the vaccine efficacy of GM-CSF-producing J558L cells, demonstrating a direct role of IL-10 in paralyzing the GM-CSF-induced antitumor immune response. Since the tumor used for challenge produced IL-10, we conclude that IL-10 interfered primarily with the initiation but not the effector phase of the immune response. Immunohistochemical analysis of the vaccine site showed a GM-CSF-induced accumulation of dendritic cells (DC) (MHC class II+ and DEC-205+) in the absence of IL-10. In the presence of IL-10, DC accumulation was completely inhibited. Together, our results demonstrate an antagonistic effect of IL-10 with respect to GM-CSF-induced DC accumulation and tumor immunity and suggest a new mechanism by which tumors escape immune recognition: namely by preventing APC from obtaining access to tumor Ags.
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PMID:Interleukin-10 prevents dendritic cell accumulation and vaccination with granulocyte-macrophage colony-stimulating factor gene-modified tumor cells. 921 94

Protection against most intracellular pathogens requires T cells that recognize pathogen-derived peptides in association with MHC class I molecules on the surface of infected cells. However, because exogenous proteins do not ordinarily enter the cytosol and access the MHC class I-processing pathway, protein-based vaccines that induce class I-restricted CTL responses have proved difficult to design. We have addressed this problem by conjugating proteins, such as OVA, to a short cationic peptide derived from HIV-1 tat (residues 49-57). When APC were exposed in vitro to such protein conjugates, they processed and presented the peptides in association with MHC class I molecules and stimulated CD8+ Ag-specific T cells. Moreover, Ag-specific CTLs were generated in vivo by immunizing mice with histocompatible dendritic cells that had been exposed to protein-tat conjugates.
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PMID:Introduction of soluble proteins into the MHC class I pathway by conjugation to an HIV tat peptide. 925 26

Dendritic cells (DC) are potent APC that may be involved in the pathogenesis of HIV-1 infection. We studied the APC function of DC from HIV-1-infected subjects that were derived from monocyte-depleted PBMC by culture in human IL-4 and human granulocyte-macrophage CSF. The cultured cells from the HIV-1-infected subjects had similar morphology and phenotype of mature DC (CD80 = 41 +/- 8%, CD86 = 77 +/- 5%, CD40 = 87 +/- 6%, CD1a = 1 +/- 1%) to DC cultured from seronegative subjects. The yield of these DC was lower than from HIV-1-seronegative subjects (4 +/- 0% vs 11 +/- 2%, p < 0.01), and the lower DC yields correlated with lower numbers of blood CD4+ T cells (r = 0.60, p < 0.01) and higher plasma viral load (r = -0.49, p < 0.01). DC from HIV-1-infected subjects were infected with recombinant vaccinia virus vectors expressing Gag, Pol, and Env and were able to stimulate equal or higher levels of MHC class I-restricted, anti-HIV-1 memory CTL (CTLm) than were similarly treated, autologous B lymphocyte cell lines. DC pulsed with peptides representing HIV-1 CTL epitopes stimulated higher levels of anti-HIV-1 CTLm responses than did DC infected with the vaccinia virus-HIV-1 constructs. Allogeneic, MHC class I-matched DC also stimulated anti-HIV-1 CTLm activity in cells from HIV-1-infected subjects. DC from early and late stages of HIV-1 infection had a similar ability to activate CTLm specific for targets expressing either HIV-1 genes via vaccinia virus vectors or HIV-1 immunodominant synthetic peptides. However, DC from either early or late stages of HIV-1 infection could not overcome the defect in anti-HIV-1 CTLm response in advanced infection.
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PMID:Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. 936 24

This paper examines functional properties of human Vgamma9/Vdelta2 T cell lines and clones generated by in vitro culture with synthetic and natural (mycobacterial) phosphoantigenic molecules. It confirms the broad reactivity of Vgamma9/Vdelta2 T cell lines and clones toward phosphoantigens. Optimal recognition of phosphoantigens by Vgamma9/Vdelta2 T cells required accessory cells to occur, but did not require specialized antigen presenting cells. However, species origin of the APC was irrelevant as proliferation of Vgamma9/Vdelta2 T cells occurred in the presence of syngeneic, allogeneic or xenogeneic APC and was not restricted to APC of particular tissue origin. Moreover antigen uptake and processing was not required for recognition by Vgamma9/ Vdelta2 cells, as evidenced by the ability of fixed APCs to present phosphoantigens. Similarly, the expression of classical MHC class I and class II molecules was not required for phosphoantigen recognition by gammadelta T cells. However, gammadelta T cell clones responded to stimulation by several cytokines including IL-12, IFNgamma and TNFalpha. Finally, Vgamma9/Vdelta2 T cell clones preferentially produced both IFN-gamma and IL-4 in response to PHA or TUBAg stimulation, revealing that a Th0 pattern of cytokine production is frequent among these cells.
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PMID:Patterns of phosphoantigen stimulation of human Vgamma9/Vdelta2 T cell clones include Th0 cytokines. 947 36


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