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

The CD28 molecule expressed on the surface of T cells plays a pivotal role in transducing costimulatory signals necessary for cell activation. CD28 coligation enhances tyrosine phosphorylation and phosphoinositol 3-kinase association in responsive cells. CD28 cross-linking has also been reported to activate inositol phospholipid turnover and to cause release of intracellular calcium. Here we examine the effects of CD28 cross-linking on early activation of protein kinase C (PKC). We have reported recently that either PMA or CD28 cross-linking synergizes with signals delivered by superantigen and cytokines to induce the proliferation of APC-depleted T cells. Unlike PMA, CD28 cross-linking alone failed to induce an increase in membrane-associated PKC activity. However, PKC activation was seen in resting T cells when CD28 was cross-linked in the presence of superantigen plus APC-derived supernatant, which by themselves had no effect on PKC activity. Inhibition of PKC activity using calphostin C blocked the response of pure T cells to superantigen in the presence of either autologous APC, PMA, or CD28 cross-linking. This effect was specific; it was only seen when calphostin C was added within the first hour of stimulation. Assays of [Ca2+]i levels showed that CD28 cross-linking augmented and prolonged the rise in [Ca2+]i induced in T cells by superantigen and APC-derived cytokines. In the presence of superantigen, the proliferative response of T cells costimulated by CD28 cross-linking was cyclosporin A-sensitive, whereas in the presence of PMA, CD28 cross-linking conferred resistance to cyclosporin A. Both the phosphorylation of phospholipase C gamma 1 at tyrosine and the rise in [Ca2+]i induced by CD28 cross-linking in preactivated T cells were blocked by herbimycin A. Herbimycin A treatment also blocked the ability of CD28 cross-linking to induce a rise in [Ca2+]i in resting T cells. We conclude that CD28 costimulatory signals augment superantigen-induced TCR signals by converging onto common TCR effector pathways involving the activation of phospholipase C gamma 1 and PKC and by generating a cyclosporin A-sensitive pathway.
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PMID:CD28 cross-linking augments TCR-mediated signals and costimulates superantigen responses. 753 90

Development of T cells during primary responses was investigated using pigeon cytochrome C-specific naive Th from TCR transgenic mice. Naive CD4 cells did not activate and help resting B cells. This failure was found to be primarily because the resting B cells were incapable of stimulating the naive Th. Provision of a costimulatory signal such as anti-CD28, or addition of APCs that express costimulatory molecules, such as dendritic cells, activated B cells, and B7+ and B7+ICAM(+)-expressing fibroblasts, induced naive Th activation and promoted T cell-dependent help for IgM secretion. T cell activation for as little as 24 h promoted helper activity, and Ig secretion required production of small amounts of IL-4 by the activated naive Th. On initial stimulation, naive Th secrete only IL-2. By mRNA analysis, activated naive Th were also shown to produce IL-4, however induction of IL-4 message only occurred 24 h after initial activation and required additional stimulation with Ag. A single exposure of naive CD4 to Ag/APC followed by 4 to 12 days in culture led to generation of effector Th which secreted IL-2 and some IFN-gamma, and no detectable IL-4 or IL-5, and which could only help B cells to IgM secretion. In contrast, similar cultures that received Ag/APC one or more times during this period generated effector cells capable of secreting easily detectable titers of IL-4 and IL-5, as well as IL-2 and IFN-gamma, and able to now promote IgG1 and IgE responses. Generation of these Th0-like effectors was accompanied by increasing amounts of IL-4 secreted during the culture period after each restimulation, and addition of anti-IL-4 in culture inhibited development of the capacity to produce Th2 cytokines. These studies reinforce the notion that naive CD4 must interact with a costimulatory professional APC, rather than a resting B cell, for initiation of the primary response, but show that such an interaction can result in rapid development of the ability to interact with and provide cognate help to B cells. They also suggest that if activated naive CD4 cells receive multiple stimulations from Ag/APC, enough endogenous IL-4 can be produced to drive differentiation into effectors secreting type 2 cytokines. The existence of such an autocrine feedback mechanism suggests that the amount and availability of Ag could influence the nature and polarization of the Th response.
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PMID:Recently activated naive CD4 T cells can help resting B cells, and can produce sufficient autocrine IL-4 to drive differentiation to secretion of T helper 2-type cytokines. 753 67

Efficient initiation of a CD4 T cell response requires both activation through the TCR and costimulation provided by molecules on APC with counterreceptors on the T cell. We investigated the relative contribution of the ICAM-1:LFA-1 and B7:CD28/CTLA-4 costimulatory pathways in naive T cell activation, using either anti-CD28 Ab or fibroblast cell lines transfected with I-Ek, which express either no costimulatory molecules, ICAM-1 alone, B7-1 alone, or ICAM-1 and B7-1 together. Peptide Ag or immobilized anti-CD3 was used to provide the TCR signal. CD4 T cells from mice transgenic for the V beta 3/V alpha 11 TCR, which recognize a peptide of pigeon cytochrome c complexed to I-Ek, were used as a source of naive T cells. Naive T cells stimulated with Ag or anti-CD3 responded well to high numbers of APC expressing either ICAM-1 alone or B7-1 alone. However, APC expressing both ICAM-1 and B7-1 were much better stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers, indicating a synergy between the two pathways. Stimulation provided by ICAM-1 could not be solely attributed to adhesive strengthening of other pathways, since costimulation was seen when immobilized anti-CD3 was used and when ICAM-1 only APC were added, indicating that ICAM-1 was in fact acting as a classic costimulatory molecule. Both the magnitude of the response and the amount of costimulation required for response were dependent on the intensity of TCR interaction. These results suggest that an efficient naive T cell response requires both a strong TCR signal and more than one costimulatory signal that will synergize with the TCR signal. This offers an explanation as to why APC such as dendritic cells and activated B cells, which express high levels of multiple costimulatory/adhesion molecules, are the only APC that elicit naive T cell responses.
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PMID:Costimulatory requirements of naive CD4+ T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. 754 26

One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.
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PMID:HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71). 754 27

Engagement of the TCR/CD3 complex together with ligation of CD28 by its counterstructures B7-1 (CD80) and B7-2 (CD86) on APC are required for mitogenic T cell activation. After activation, T cells not only express B7-1 and B7-2 molecules, but a second receptor for the B7 ligands, CTLA-4, can be found on their surfaces. We here show that B cells can be induced to express CTLA-4 on the plasma membrane. Similar to what has been reported for T cells, CTLA-4 expression on B cells was transient. Purified B cells did not express CTLA-4 when mitogenically activated with alpha IgM and CD40 Ab, but did express the molecule when cultured in the presence of membranes from activated T cells, which suggests that induction of CTLA-4 expression on B cells was dependent on direct cell-cell contact of B lymphocytes and activated T cells. CTLA-4 molecules isolated from either T or B cells were biochemically indistinguishable. Moreover, because the ability of chimeric B7-1/Ig proteins to bind to activated B cells was correlated with CTLA-4 expression levels on these cells, we conclude that B cell-expressed CTLA-4 has ligand binding capacity. These data suggest that costimulatory receptors and their specific ligands not only play a role in T cell stimulation, but contribute in a direct fashion to the regulation of B cell responses.
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PMID:Activated T cells can induce high levels of CTLA-4 expression on B cells. 754 32

Activation of T lymphocytes can result in a functional immune response, anergy or apoptosis. Functional T cell activation requires the interaction of the TCR with Ag presented by MHC molecules on APC concurrent with appropriate interactions between cell surface accessory molecules. Interestingly, the level of CD28 expression is regulated during T cell development as well as during T cell activation and proliferation, suggesting that CD28 could play a role in determining the outcome of activation of TCR during T cell ontogeny. We identify, herein, a novel function of murine CD28 in the regulation of activation-induced apoptosis in thymocytes. In vivo, or combined in vivo and in vitro treatment with mAbs to CD28 prevents apoptosis of CD4+CD8+ thymocytes induced by Abs to the TCR complex. Prolonged administration of anti-CD28 Abs increased the number of both CD4+CD8- and CD4-CD8+ T cells in the thymus, while the number of CD4+CD8+ T cells is relatively unchanged. Furthermore, this treatment leads to a dramatic enlargement of peripheral lymphoid organs characterized primarily by the expansion of B cells. The number of CD4+CD8- T cells in the spleen of anti-CD28-treated mice is also moderately increased, while the number of CD4-CD8+ cells is relatively unchanged.
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PMID:CD28-mediated signaling in vivo prevents activation-induced apoptosis in the thymus and alters peripheral lymphocyte homeostasis. 754 34

In previous studies, we have shown that ultraviolet (UV) B radiation perturbs the APC function of Langerhans cells (LC) by interfering with as-yet unidentified co-stimulatory signals. Recently, B7.1 and B7.2 on APC were shown to deliver important co-stimulatory signals through interaction with their counter receptors CD28 and CTLA-4 on T cells. To determine whether UVB affects the functional expression of B7.1 or B7.2 on LC, B7.1 and B7.2 expression was studied on human LC by multiparameter flow cytometry. Little, if any, B7.1 or B7.2 was detected on LC freshly isolated from skin. However, following 48 h of tissue culture, expression of both B7.1 and B7.2 were markedly up-regulated. To test whether these molecules were functional, primary mixed epidermal cell leukocyte reactions (MECLR) were performed. Blocking monoclonal antibody (mAb) to B7.1 or B7.2 both inhibited the MECLR, with anti-B7.2 being much more effective than anti-B7.1. UVB radiation dose-dependently (100-200 J/m2) suppressed the culture-induced up-regulation of B7.1 and B7.2 on LC. Since LC exposed to the same UVB flux (UVB-LC) failed to stimulate alloreactive T cells in a MECLR, we questioned whether this was related to their inability to provide B7 co-stimulation. Indeed, when effective B7-CD28 signaling was ascertained by adding submitogenic doses of exogenous anti-CD28 mAb to UVB-LC, the proliferative response of alloreactive T cells was restored. We conclude that the suppressive effects of low-dose UVB radiation on the APC function of LC are, at least in part, due to an inhibition of functional B7.1 and B7.2 expression.
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PMID:Low-dose UVB radiation perturbs the functional expression of B7.1 and B7.2 co-stimulatory molecules on human Langerhans cells. 758 83

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

Staphylococcal enterotoxins, also known as superantigens (SAg), bind class II MHC molecules on APC and upon direct cell-to-cell contact stimulate proliferation of T cells expressing appropriate V beta gene products. The T cell surface molecule CD28 binds its costimulatory counter-receptor, B7 expressed on APC, and augments IL-2 production and T cell growth. Although the role of B7 costimulation during Ag-specific responses of T cells is established, its involvement during the activation of T cells with SAg has not been examined. Using a soluble Ig C gamma 1 chimera of CTLA-4, a second receptor for B7 and a homologue of CD28, this study examines the role of B7 expressed on APC during the induction of proliferation of CD4+ T cells upon stimulation with SAg (SAg/staphylococcal enterotoxins). CTLA-4lg, which has a higher avidity for B7 than CD28, had no effect on the synthesis of IL-2 as well as proliferative responses of CD4+ T cells induced by SAg presented on allogeneic EBV-transformed B cells, and IFN-gamma-activated endothelial cells. In contrast, T cell proliferation induced by alloAg presentation by the same APC was significantly inhibited by CTLA-4lg. mAb directed at the CD11a/CD18 molecule inhibited both SAg-induced and alloAg-induced proliferation of T cells. AlloAg-primed CD4+ T cells, which expressed both class II MHC and intercellular adhesion molecule-1 but not B7, presented SAg to and induced proliferation of both resting and SAg-primed T cells. These responses were inhibited by mAb directed at CD11a/CD18 but not by CTLA-4 Rg. These results suggest that SAg-induced responses differ from those induced by alloAg in that they are not obligatorily dependent on the costimulation by B7. In contrast, adhesive interaction between CD11a/CD18 on T cells and its counter-receptor on SAg-presenting cells is necessary and probably sufficient to support SAg-induced proliferation of T cells.
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PMID:Proliferation of human T lymphocytes induced with superantigens is not dependent on costimulation by the CD28 counter-receptor B7. 767 19


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