UMLS:C0033036 - FACTA Search

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

The function of gamma delta T cells, particularly the minor population of circulating gamma delta T cells, remains unclear. To study these lymphoid gamma delta T cells, a transgenic SCID mouse containing the KN6 gamma delta TCR whose ligand is the TL gene product, T22b, was created. KN6-SCID mice contain a monoclonal population of naive KN6+ gamma delta T cells. Using these mice, we have studied the APC required for activation of KN6+ gamma delta T cells in vitro and in vivo. Analysis of an in vitro mixed lymphocyte response identified a hierarchy of potency for stimulation: dendritic cells = T cell blasts > B cell blasts > B cells > resting T cells. In contrast, in vivo, only alpha beta T cells fully activated KN6+ gamma delta T cells as measured by an increase in the number of splenic KN6+ cells, the development of blast morphology, and the development of proliferative anergy in the responding KN6+ cells. The strong stimulatory properties of C57BL/6J T cells appeared to depend on their having been activated by KN6-SCID alloantigens. T cells from (C57BL/6J x BALB/c)F1 mice, which are tolerant of KN6-SCID alloantigens, could not fully activate KN6+ cells. However, the F1 T cells could activate KN6+ cells if they were activated in vivo by the mitogen, staphylococcal enterotoxin B. A mixture of third party activated T cells plus T22b+ non-T cells only partially activated KN6+ cells, implying that activated T22b+ T cells are acting directly as stimulatory cells. Although the Ags recognized by gamma delta T cells are generally unknown, Ag presentation by activated alpha beta T cells may be an important method of activation.
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PMID:Antigen-presenting cells for naive transgenic gamma delta T cells. Potent activation by activated alpha beta T cells. 756 Oct 93

Most instances of MHC class I recognition and target cell killing by CD8+ CTL require the involvement of CD8. The role of CD8 in these events may be both for adhesion of the CTL with the APC, as well as for signal transduction through the TCR. The precise mechanism by which CD8 mediates signal transduction remains enigmatic. Similarly, it is unclear whether only the CD8 molecules which bind to the same class I molecule as the TCR contribute to signaling in the T cell responding to antigen. We have investigated the requirement for co-engagement of CD8 and the TCR in the induction of the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) during the interaction of CTL and APC transfected with either wild-type or mutant (CD8 non-binding) class I molecules. Our results show that for conventional CD8-dependent killing co-engagement of both CD8 and the TCR is required to initiate PIP2 hydrolysis. This requirement for co-engagement, however, can be overcome by a high density of ligand, such as that provided by high concentrations of exogenous peptide. In such situations, the binding of CD8 to non-antigenic class I molecules can elicit PIP2 hydrolysis. Therefore, during interactions between CTL and APC, which generally occur at low concentrations of antigenic peptide, triggering of PIP2 hydrolysis requires TCR and CD8 co-engagement, and the binding of CD8 to non-antigenic class I molecules does not contribute significantly to signaling within the T cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:CD8-dependent CTL require co-engagement of CD8 and the TCR for phosphatidylinositol hydrolysis, but CD8-independent CTL do not and can kill in the absence of phosphatidylinositol hydrolysis. 757 8

Ligand-directed differences in the amount of peptide presented on a specific APC subset could influence the functional outcome of any given immune response. We have investigated this issue with a biochemically determined immunodominant peptide that is presented at a higher density on the APC of Th1 responders (I-As genotypes) than on the APC of Th2 responders (I-Ab genotypes). MHC-linked high peptide density is expressed on B lymphocytes, predominantly those that bear the B7-2 activation marker/costimulatory ligand. We further investigated the role of I-As-specific polymorphism with transfected cells bearing an R-->Q change at position-70 of A beta (found only in the I-As allele). Strikingly, I-Ab-restricted Th1 and Th2 clones proliferate at a peptide dose 10- to 100-fold lower than wild-type on transfected fibroblasts bearing this single s-like substitution in A beta b. Moreover, the shift in the clone dose response is sensitive to the peptide's C-terminus, as is MHC-linked Th1-like immunity to this peptide in vivo. Together, these data suggest that ligand-density can dictate Th1/Th2 selection via a single MHC polymorphism that determines the level of peptide presented to a given TCR on activated B cells.
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PMID:High-density presentation of an immunodominant minimal peptide on B cells is MHC-linked to Th1-like immunity. 758 85

Partially inbred, MHC homozygous miniature swine have been used to study the nature of the human xenogeneic cellular immune response to swine Ags in vitro. Human T cells responded to xeno-MHC Ags in MLR at least as well as they did to allo-MHC Ags and appeared to share similar requirements for APC of either stimulator (direct pathway) or responder (indirect pathway) derivation. In addition, mAb-blocking experiments indicated that the majority of the primary human anti-pig xeno-response was directed toward porcine MHC class II Ags and involved interaction with the human CD4 accessory molecule. Finally, the availability of intra-MHC recombinant haplotypes in our herds has made it possible to map genetically the antigenic specificities recognized in human anti-swine cellular responses. For this purpose, T cell clones were generated from human anti-swine MLR cultures and were tested for reactivity to stimulator cells from MHC homozygous and recombinant haplotypes. Clear evidence for antixenogeneic MHC Ags was observed. In all cases in which allelic differences between haplotypes were detected (the majority of clones), the reactivity could be mapped to the class II region of stimulator haplotypes. In addition, cross-reactivity between haplotypes was consistent with known sequence similarities between DR beta-chains. Our results indicate, therefore, that the human anti-porcine T cell response is similar in strength and specificity to an allogeneic response, and that the TCR repertoire, accessory molecule interactions, and cytokine production required for both direct and indirect pathways of recognition in the human anti-porcine MHC class II responses are functionally intact.
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PMID:Human anti-porcine xenogeneic T cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition. 759 37

The induction of anergy in T cells is believed to be the result of triggering of the TCR in the absence of adequate costimulation mediated through the interaction of CD28 and its ligands, CD80 and CD86. Here, we demonstrate that stimulation of human group I allergen in Dermatophagoides pteronyssinus extract (Der p 1)-specific CD4+ Th2-like T cell clones with Der p 1-derived peptides in the absence of professional APC results in a state of nonresponsiveness. The induction of anergy occurred despite the expression of high levels of CD28, CD80, and CD86 on the surface of the T cell clones and was not prevented by the addition of anti-CD28 mAb. The anergic, Der p 1-specific, Th2 cells failed to mobilize calcium from intracellular stores, to proliferate, and to produce IL-2, IL-4, IL-13, GM-CSF, and TNF-alpha following optimal stimulation with Der p 1-derived peptide and autologous APC. However, they mobilized intracellular calcium following stimulation with Ca(2+)-ionophore and produced all of the above cytokines, including IFN-gamma, when stimulated with phorbol ester and Ca2+ ionophore. These results indicate that the anergic T cell clones are capable of responding to signals circumventing the TCR/CD3 complex activation pathway. In contrast to T cell clones optimally activated with peptide and APC, anergic T cells failed to induce IgG4 and IgE synthesis when cocultured with B cells, even in the presence of exogenous IL-4 or IL-13. Anergic T cells expressed normal levels of CD40L, suggesting that their inability to help in Ig production by B cells is due to conditions other than a lack of expression of this molecule. Finally, exogenous IL-2 restored the helper function of anergic Th2 T cells for IgE production by B cells, which was greatly enhanced by the addition of IL-4 or IL-13. These data suggest that induction of anergy in allergen-specific Th2 T cells by allergen-derived peptides may play an important role in the successful desensitization of allergic patients.
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PMID:Peptide-induced anergy in allergen-specific human Th2 cells results in lack of cytokine production and B cell help for IgE synthesis. Reversal by IL-2, not by IL-4 or IL-13. 759 75

The bacterial superantigen staphylococcal enterotoxin B (SEB) induces in vivo a state of anergy defined by the inability of V beta 8+ CD4+ T cells to produce IL-2 upon restimulation in vitro. However, restimulation in vivo triggers a burst of acutely released lymphokines including IL-2 and TNF, paralleled by up-regulation of lymphokine-specific mRNA. Since anergy as defined in vitro appears not to operate in vivo, we analyzed parameters able to induce responsiveness in anergic T cells. We show here that in vitro stimulation of anergic T cells with competent Ag-presenting cells induces responsiveness, provided the APC (activated B cells or dendritic cells) present high concentrations of SEB. Crosslinking of CD28 molecules on anergic T cells could substitute the requirement for competent APC. Quantitation of TCR threshold by determining the SEB concentrations able to trigger half-maximal T cell responses revealed that anergic and normal T cells exhibited the same TCR threshold for the expression of functional IL-2 receptors (IL-2R), yet the TCR threshold for induction of IL-2 production was 10- to 100-fold elevated in anergic T cells. TCR threshold for normal and anergic T cells was further dependent on the type of APC, i.e., costimulus-competent APC required 100-fold less SEB. The results indicate that extrinsic factors such as ligand concentration and costimulus competence of APC can overcome the heightened TCR threshold of anergic T cells, thus reverting anergy into responsiveness.
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PMID:Induction of responsiveness in superantigen-induced anergic T cells. Role of ligand density and costimulatory signals. 760 25

Transforming growth factor beta (TGF-beta) exhibits diverse effects on growth and differentiation of a wide range of cell types. In the immune system, TGF-beta 1 is a potent inhibitor of T cell proliferation and certain T cell effector functions. However, TGF-beta 1 also enhances growth of T cells, predominantly of naive phenotype, and induces their expression of selected cytokines. We have previously demonstrated that TGF-beta 1 costimulates growth of highly purified murine CD8+ T cells activated by immobilized anti-CD3 Ab. TGF-beta 1-costimulated CD8+ T cells rapidly express a memory phenotype, lose lytic function, and express a mixed cytokine pattern with IL-2, IFN-gamma, and appreciable IL-10, as well as TGF-beta 1. The present work examines the possibility that TGF-beta 1 similarly costimulates response of murine CD8+ T cells to the microbial superantigen staphylococcal enterotoxin B (SEB) and characterizes their effector and regulatory functions. TGF-beta 1 significantly enhances CD8+ T cell proliferation to SEB in the presence of MHC class II-positive APC and TGF-beta 1-primed CD8+ T cells are enriched for SEB-reactive V beta 8+ TCR expression. TGF-beta 1 priming also up-regulates a memory-like CD45RBlowCD44highMEL-14low phenotype. TGF-beta 1 priming inhibits development of SEB-specific lytic effector function by more than 90%. However, TGF-beta 1-primed CD8+ effector T cells express elevated levels of IL-10 and TGF-beta 1, variable IFN-gamma, and undetectable IL-4. Additionally, they exhibit growth inhibitory effector function of SEB-induced proliferation of other CD4+ and CD8+ T cells. Growth inhibition by TGF-beta 1-primed CD8+ T cells is reversed in part by anti-IL-10 Ab. Thus, in the context of SEB response, TGF-beta 1 promotes the outgrowth and induces the effector function of CD8+ T cells that have the capacity to impair T cell clonal growth.
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PMID:Transforming growth factor beta 1 costimulated growth and regulatory function of staphylococcal enterotoxin B-responsive CD8+ T cells. 760 39

Although superantigens and their molecular interactions with MHC class II molecules have been well characterized recently, little is known concerning the physiological function of different types of APC in inducing superantigen-mediated T cell activation. To evaluate the potential of nonhematopoetic cells to present superantigens to T cells, we have tested astrocytes as a typical "nonprofessional" APC. Although astrocytes can express appropriate levels of MHC class II products and adhesion molecules, they turned out to be unable to mediate superantigen-driven activation of normal T lymphocytes, even in the presence of rather high concentrations of toxins. In contrast, they could properly present equimolar amounts of nominal Ag to various Ag-specific T cell lines under the same experimental conditions. Inability of astrocytes to support T cell responses to superantigens could not be overcome by addition of cytokines IL-1 and IL-6. Binding studies with class II-expressing astrocytes revealed that T cell unresponsiveness was not due to a general failure of astrocytes to bind the superantigen. Moreover, the resulting SA-class II complex was recognizable by TCR, as demonstrated by the capacity to activate IL-2 secretion in T cell hybridomas. Our results extend previous studies demonstrating marked differences of various types of APC to trigger T cell responses to superantigens and describe for the first time a dissociation of the Ag-presenting capacity for peptide-Ag vs superantigen on an accessory cell.
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PMID:Dissociation of antigen-presenting capacity of astrocytes for peptide-antigens versus superantigens. 767 36

Costimulatory molecules on the APC regulate T cell growth by providing signals that regulate responses to TCR occupancy. One such molecule is B7/BB-1, which triggers a T cell activation pathway by binding the CD28 and/or CTLA-4 cell-surface molecules. Expression and signaling activity of CD28 have been shown to increase after T cell activation by various polyclonal activators. Here we show that CD28 expression and signaling activity in activated T cells decrease after ligand binding to CD28. Stimulation of CD28 on PHA- or PMA-activated T cells by cross-linked mAb 9.3 or by co-culture with B7+ Chinese hamster ovary (CHO) cells caused a marked reduction of CD28 mRNA levels within 4 h. The decrease in CD28 mRNA was transient, and by 24 h of CD28 stimulation, CD28 mRNA was found at approximately initial levels. In contrast, CTLA-4 mRNA levels were usually up-regulated by CD28 triggering. Cell-surface expression of CD28, but not CD2 or CD3, decreased by 12 to 24 h after addition of B7+ CHO cells, but returned to initial levels or higher by 48 h. The ability of CD28 cross-linking on PMA-activated CD4+ cells to trigger calcium mobilization was also reduced by treatment with B7+ CHO cells, and remained reduced even after cell-surface expression of CD28 returned to normal levels. Thus, engagement of the CD28 receptor by its natural ligand B7/BB-1 leads to a transient down-regulation of CD28 synthesis and a prolonged unresponsiveness to CD28 signaling. This represents a novel mechanism for regulation of costimulatory signals delivered by interactions of CD28 with the B7/BB-1 counter receptor.
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PMID:CD28 engagement by B7/BB-1 induces transient down-regulation of CD28 synthesis and prolonged unresponsiveness to CD28 signaling. 768 33

The CD28 pathway functions to provide costimulatory signals that are required for TCR-mediated activation of T cells. The role of this pathway in superantigenic stimulation of resting human T cells was investigated in the presence and absence of APC using a streptococcal superantigen, pep M5. Anti-B7/BB1 mAb inhibited the response of T cells when pep M5 was presented by APC. In the absence of APC, cross-linking CD28 by anti-CD28 mAb provides signals that synergize with APC-derived cytokines and with superantigen resulting in T cell proliferation. Anti-HLA-DR, -DQ mAb blocked the response of T cells to pep M5 presented by APC but had no effect on the response of purified T cells to the superantigen costimulated via CD28 cross-linking. These data show that the CD28 pathway is important for superantigenic stimulation of T cells and that signaling through this pathway can substitute for the APC-associated costimulatory activity that is essential for T cell stimulation. Moreover, the results are consistent with the notion that, in the presence of appropriate costimulation, pep M5 can directly interact with T cells and induce them to proliferate.
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PMID:CD28 delivers costimulatory signals for superantigen-induced activation of antigen-presenting cell-depleted human T lymphocytes. 768 35

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