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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD4+ T cells require two signals to produce maximal amounts of IL-2, i.e., TCR occupancy and an unidentified APC-derived costimulus. Here we show that this costimulatory signal can be delivered by the T cell molecule CD28. An agonistic anti-CD28 mAb, but not IL-1 and/or IL-6, stimulated T cell proliferation by tetanus toxoid-specific T cells cultured with Ag-pulsed, costimulation-deficient APC. Furthermore, the ability of B cell tumor lines to provide costimulatory signals to purified T cells correlated well with expression of the CD28 ligand B7/BB-1. Finally, like anti-CD28 mAb, autologous human APC appeared to stimulate a cyclosporine A-resistant pathway of T cell activation. Together, these results suggest that the two signals required for IL-2 production by CD4+ T cells can be transduced by the TCR and CD28.
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PMID:CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. 171 61

T cell epitopes can be defined by the use of synthetic peptides, which when added to APC efficiently mimic naturally processed Ag. Free peptide is thought to bind to cell-surface MHC glycoproteins and the TCR then recognizes the resulting complex. The specificity of a tetanus toxin-specific human Th cell clone was investigated using a complete replacement set of peptides in which every amino acid within the minimal T cell epitope was replaced by each of the 19 alternative genetically coded amino acids. Within the minimal epitope, found to be YSYFPSVI (tetanus toxin 593-600), a small number of substitutions could be made without significant loss of activity, defined as substitutions giving peptides whose activity fell within +/- 3 SD of the mean parent response. Y593 could be substituted with F, W, M, L, V, and I; S594 with G and T; Y595, F596, and P597 with no other amino acids; S598 with A; V599 with S, and I600 with L. Rank ordering of the substitutions allowed a precise description to be made of MHC and/or TCR interaction with each amino acid side chain within the epitope. Simplified theoretic calculations based on this study indicate that class II T cell recognition has a specificity greater than 1 in 10(8). Competition experiments indicate that Y595, F596, P597, and I600 are critical for binding of this epitope to its restricting element, HLA DR4Dw14.
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PMID:Role of single amino acids in the recognition of a T cell epitope. 171 63

The thymus is the primary organ in which T cells undergo rearrangement of T cell receptor alpha and beta genes, positive selection for affinity to self MHC products, and elimination (negative selection) of reactivity to self antigens. These events require an interaction of the developing T cell with other cell types in the thymus. The latter include epithelial cells, macrophages, dendritic cells, and the recently described thymic B cells the majority of which are CD5+. Here we review the identification and isolation of thymic dendritic cells and CD5+ B cells. We consider phenotype, ontogeny, and function, including possible contributions to the induction of self tolerance. Thymic dendritic cells are similar to spleen dendritic cells, but are larger and exhibit a few differences in phenotype. Dendritic cells from both organs are equally potent accessory cells for the MLR and lectin-induced, T cell proliferation. Thymic dendritic cells have higher levels of Fc receptors and support anti-CD3 dependent mitogenesis. Thymic CD5+ B cells share phenotypic features with peritoneal CD5+ B cells. However thymic B cells neither proliferate nor form antibody producing cells in response to the stimulation with LPS or anti-IgM plus IL-4, but do respond to stimulation with MHC class II-restricted helper T cells. Thymic dendritic cells and CD5+ B cells both appear at a similar time in ontogeny, about 14 d of gestation, which is the time T cell differentiation begins to take place. Dendritic cells from spleen, which are potent activators for peripheral T cells, are also potent inactivators for thymic-derived cytotoxic T cells. A correlation between reactivity to MIs products and the expression of TCR-V beta genes is well documented, and B cells are the primary APC for this antigen. Therefore, thymic CD5+ B cells may be a good tool for the investigation of tolerance to M1s products.
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PMID:Thymic dendritic cells and B cells: isolation and function. 172 38

Murine IL-10 (cytokine synthesis inhibitory factor) inhibits cytokine production by Th1 cell clones when they are activated under conditions requiring the presence of APC. By preincubating APC with IL-10, we demonstrate that IL-10 acts principally on APC to inhibit IFN-gamma production by Th1 clones. Moreover, IL-10 is not active when Th1 cells are stimulated with glutaraldehyde-fixed APC, which also indicates that its action involves regulation of APC function. Furthermore, IL-10 inhibits cytokine synthesis by Th1 cells stimulated with the super-antigen Staphylococcus enterotoxin B, which does not appear to require processing. Flow microfluorimetry purified splenic or peritoneal B cells and macrophages, and B cell and macrophage cell lines can present Ag to Th1 clones. However, IL-10 acts only on sorted macrophages and the macrophage cell line to suppress IFN-gamma production by Th1 clones. IL-10 does not show this effect when B cells are used as APC. In contrast, IL-10 does not impair the ability of APC to stimulate cytokine production by Th2 cells. IL-10 does not decrease IFN-gamma-induced I-Ad levels on a macrophage cell line. Inasmuch as IL-10 also inhibits IL-2-induced IFN-gamma production by Th1 cells in an Ag-free system requiring only the presence of accessory cells, these data suggest that IL-10 may inhibit macrophage accessory cell function which is independent of TCR-class II MHC interactions.
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PMID:IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. 182 84

In nonobese diabetic (NOD) mice, T cells play a major role in mediating autoimmunity against pancreatic islet beta-cells. We and others previously reported that age-related alterations in the thymic and peripheral T cell repertoire and function occur in prediabetic NOD mice. To study the mechanism responsible for these T cell alterations, we examined whether a defect exists in the thymus of NOD mice at the level of TCR-mediated signaling after activation by Con A and anti-CD3. We found that thymocytes from NOD mice respond weakly to Con A- and anti-CD3-induced proliferation, compared with thymocytes from control BALB/c, BALB.B, (BALB.B x BALB.K)F1, C57BL/6, and nonobese non-diabetic mice. This defect correlates with the onset of insulitis, because it can be detected at 7 to 8 weeks of age, whereas younger mice displayed a normal T cell responsiveness. Thymic T cells from (NOD x BALB/c)F1 mice, which are insulitis- and diabetes-free, exhibit an intermediate stage of unresponsiveness. This T cell defect is not due to a difference in the level of CD3 and IL-2R expression by NOD and BALB/c thymocytes, and both NOD CD4+ CD8- and CD4- CD8+ mature thymic T cells respond poorly to Con A. BALB/c but not NOD thymic T cells respond to Con A in the presence of either BALB/c or NOD thymic APC, suggesting that the thymic T cell defect in NOD mice is intrinsic to NOD thymic T cells and is not due to an inability of NOD APC to provide a costimulatory signal. The defect can be partially reversed by the addition of rIL-2 to NOD thymocytes. To determine whether a defect in signal transduction mediates this NOD thymic T cell unresponsiveness, we tested whether these cells elevate their intracellular free Ca2+ ion concentration in response to Con A. An equivalent Con A-induced increase in Ca2+ ion concentration in both NOD and BALB/c thymocytes was observed, suggesting a normal coupling between the CD3 complex and phospholipase C in NOD thymocytes. In contrast to their low proliferative response to Con A or anti-CD3, NOD thymocytes respond normally (i.e., as do BALB/c thymocytes) to the combinations of PMA plus the Ca2+ ionophore ionomycin and PMA plus Con A but weakly to Con A plus ionomycin. Our data suggest that the age-related NOD thymocyte unresponsiveness to Con A and anti-CD3 results from a defect in the signaling pathway of T cell activation that occurs upstream of protein kinase C activation.
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PMID:Defective thymic T cell activation by concanavalin A and anti-CD3 in autoimmune nonobese diabetic mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis. 182 15

Autocrine growth of Th type 2 cells has been reported to be mediated by the lymphokine IL-4. In this report we present evidence that in addition to IL-4 Th2 cells also produce IL-1 alpha in its active form in the absence of APC. We have found that this cytokine is an autocrine growth factor, because proliferation of Th2 cells in response to several stimuli is inhibited by anti-IL-1 alpha or anti-IL-1R mAb, or by an IL-1 alpha antisense oligodeoxynucleotide. However, Th1 cells do not produce this cytokine. We have investigated the role of endogenous IL-1 alpha on the induction of c-myc and c-myb, two protooncogenes involved in T cell activation. Here we show that endogenous IL-1 alpha is involved in the activation of both protooncogenes. Our results suggest that a possible function of IL-1 alpha, and perhaps other growth factors, might be to sustain or amplify the initial second messengers derived through the TCR. The possible implications of this finding with respect to interactions between T cell subsets and B cells or macrophages are discussed.
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PMID:Production of IL-1 alpha by activated Th type 2 cells. Its role as an autocrine growth factor. 182 18

Induction of peripheral T cell anergy associated with stimulation through the TCR complex in vivo has been described in mice using chemically modified APC, staphylococcal enterotoxin B, and intact anti-CD3 mAb. In the latter two models, T cell proliferation, IL-2R expression, and lymphokine production have been demonstrated before subsequent induction of hyporesponsiveness, whereas in the former model, these events have not been observed. To further investigate the relationship between mitogenicity and induction of peripheral hyporesponsiveness, mice were treated with either mitogenic intact anti-CD3 mAb or nonmitogenic F(ab')2 fragments of anti-CD3 mAb. T cells from F(ab')2-treated mice demonstrated a selective decrease in helper functions, with minimal effect on CTL function. Specifically, a marked reduction in ability of Th cells to secrete IL-2 when challenged in vitro with mitogen or alloantigen was observed, which persisted for at least 2 mo after mAb administration and which was independent of T cell depletion. Proliferative function was decreased in CD4+ T cells and could not be fully restored with addition of exogenous IL-2. A helper defect was also evident in vivo, in that F(ab')2-treated mice were deficient in their ability to reject MHC-disparate skin grafts, and in vivo administration of IL-2 reconstituted their ability to reject skin grafts normally. In contrast, T cells from mice treated with intact mAb demonstrated a significant decrease in both CTL and helper functions. A long term reduction in TCR expression on CD4+ cells from F(ab')2-treated mice, and on both CD4+ and CD8+ cells from intact mAb-treated mice was observed. These findings demonstrate that peripheral T cell hyporesponsiveness can be induced in vivo by binding an identical epitope on the TCR complex in the presence or absence of initial proliferation, lymphokine secretion, or IL-2R expression, and that binding to the same epitope can result in varying long term effects on T cell function.
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PMID:Differential T cell hyporesponsiveness induced by in vivo administration of intact or F(ab')2 fragments of anti-CD3 monoclonal antibody. F(ab')2 fragments induce a selective T helper dysfunction. 183 51

We have investigated the interaction between murine T lymphocytes and allogeneic APC in an in vitro proliferative mixed leukocyte reaction. Our results demonstrate that freshly isolated potentially alloreactive murine splenic T lymphocytes, in primary culture, can be induced to develop a state of allospecific proliferative hyporesponsiveness in vitro by exposure to 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-modified allogeneic APC, a method similar to that previously used to induce nonresponsiveness in murine Ag-specific self-MHC-restricted T lymphocyte clones. This hyporesponsiveness was: specific for the allohaplotype of inducing APC, maintained for 96 h in vitro, not due to cellular inhibitory mechanisms, and associated with reduced ability to secrete IL-2 but not IL-3. Induction of this hyporesponsiveness was not due to altered expression of class II MHC gene products on the APC but was associated with markedly reduced T lymphocyte-APC adhesive interactions despite the lack of a detectable immunophenotypic change in lymphocyte function-associated Ag 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) expression on the modified APC. Therefore, we propose that TCR occupancy in the absence of normal T lymphocyte-APC adhesive clustering may induce T lymphocyte tolerance.
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PMID:Chemically modified antigen-presenting cells induce T lymphocyte allospecific hyporesponsiveness. 183 77

In Th1 clones, TCR occupancy together with a costimulatory signal from APC results in IL-2 production. TCR occupancy alone results in unresponsiveness (anergy) to antigenic stimulation, a phenomenon that may be important for self-tolerance in vivo. Inasmuch as inositol phosphate production occurs during the induction of anergy other biochemical signals must be necessary for IL-2 production. Here we assess the role of tyrosine-specific protein kinases using the specific inhibitor, genistein. IL-2 secretion and responsiveness were very dependent on tyrosine-specific protein kinase activation and could be completely blocked under conditions where inositol phosphate generation occurred normally. Although anergy induction could also be blocked by inhibition of tyrosine-specific protein kinase activation this probably occurred indirectly via inhibition of inositol phospholipid hydrolysis. The differential susceptibility of IL-2 secretion and anergy induction to inhibition by genistein indicates that positive and negative outcomes of TCR occupancy may be mediated by distinct biochemical pathways.
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PMID:IL-2 secretion and T cell clonal anergy are induced by distinct biochemical pathways. 184 93

The degree to which processed self-peptides contribute to the stimulation of autoreactive T cells has not been determined. In this study we have analyzed a panel of autoreactive T cell hybridomas from normal C57BL/26 mice produced by fusing peripheral lymph node cells with a variant of the BW5147 thymoma line, which does not express endogenous TCR alpha- and beta-chains. All of the autoreactive hybridomas responded to spleen cells expressing the syngeneic I-Ab allele, but not to allogeneic spleen cells. Although all hybridomas were I-Ab restricted, they demonstrated different patterns of reactivity to a panel of APC expressing I-Ab but derived from different genetic backgrounds. In a panel of APC expressing recombinant I-A molecules, changes in the second half of the first domain, which encodes alpha-helix segments that flank the Ag binding site and directly contact the TCR V regions in proposed models, eliminated reactivity of all hybridomas tested. In addition, most of the autoreactive hybridomas also demonstrated inhibition of reactivity to mutations in the amino half of the first domain of the I-A alpha- and beta-chains, which encodes the beta-pleated sheet of the floor of the Ag-binding groove. To confirm the role of processed peptides in the different patterns of reactivity, APC were incubated with competitor Ag and fixed by glutaraldehyde cross-linking before incubation with the autoreactive T hybridomas. The hybridomas were effectively inhibited by exogenous protein and peptide Ag. These results indicate that processed self-peptides are required to activate the autoreactive T cells.
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PMID:Characterization of autoreactive T cells. Relative importance of self-peptides versus MHC. 186 Oct 76


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