Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD80 (B7-1) and CD86 (B7-2) on APC provide a major costimulatory signal through interactions with CD28 on T cells. Absent from resting human T cells, CD86 is up-regulated early upon T cell activation, whereas CD80 expression appears later. Whereas T cell expression of CD80 has been implicated in costimulation, the functional significance of CD86 expression on T cells is unclear. We now demonstrate that CD86 expressed on human CD4+ T cell clones does not provide a costimulatory signal for other CD4+ T cell clones. Binding studies using CD28-Ig and CTLA-4-Ig fusion proteins demonstrate that CD86 expressed on T cells has significantly reduced binding affinity for CTLA-4 and no detectable binding to CD28. Biochemical analysis demonstrates that post-translational modifications of CD86 in human T cells are different from those of CD86-transfected Chinese hamster ovary cells or EBV-transformed B cells, in that T cells express a hypoglycosylated form of CD86 on the surface membrane. Thus, our results suggest that while CD86 is expressed on a number of different cell types, its costimulatory function and affinity for its ligands may be regulated by cell type-specific post-translational modifications.
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PMID:Expression of a hypoglycosylated form of CD86 (B7-2) on human T cells with altered binding properties to CD28 and CTLA-4. 936 4

Cutaneous painting with reactive haptens induces contact sensitivity (CS) responses that are in vivo examples of T cell immunity. In contrast, high dose i.v. administration of the hapten can induce tolerance. We investigated the effect of IL-12 on reversal of this tolerance and attempted to determine in vitro the mechanism of this reversing effect by measuring proliferation and IFN-gamma production by CS effector T cells stimulated with hapten-conjugated APC, and we also measured CS ear swelling in vivo. The in vitro responses of T cells to hapten-APC became absent in tolerized mice, paralleling impaired in vivo CS responses. Addition of IL-12 to cultures manifesting this fully established in vitro tolerance completely restored impaired responses of tolerized T cells. The reversing effects of IL-12 were not blocked by anti-IFN-gamma mAb, but were blocked by mAbs against B7-1, more strongly by anti-B7-2, and by both Abs together. Additional in vivo ear-swelling response experiments confirmed the reversing effects of IL-12 on established tolerance. To examine whether the IL-12 effect depended on stimulation of IFN-gamma, we directly injected IFN-gamma into tolerized mice. This partially mimicked but did not fully reconstitute the effects of IL-12. In summary, IL-12 abrogation of established tolerance of CS may have been partially due to endogenous production of IFN-gamma, but appeared mainly due to direct activation of the tolerized T cells by affecting signaling through costimulatory molecules B7-1 and B7-2.
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PMID:IL-12 reverses established antigen-specific tolerance of contact sensitivity by affecting costimulatory molecules B7-1 (CD80) and B7-2 (CD86). 949 44

Allergic asthma is thought to be mediated by CD4+ T lymphocytes producing the Th2-associated cytokines, IL-4, and IL-5. Recently, the costimulatory molecules B7-1 and B7-2, which are expressed on the surface of APC, have been suggested to influence the development of Th1 vs Th2 immune responses. We examined the in vivo role of these costimulatory molecules in the pathogenesis of Th2-mediated allergen-induced airway hyperresponsiveness in a murine model of asthma. In this model, OVA-sensitized A/J mice develop significant increases in airway responsiveness, pulmonary eosinophilia, and pulmonary Th2 cytokine expression following aspiration challenge with OVA as compared with PBS-control animals. Strikingly, administration of anti-B7-2 mAb to OVA-treated mice abolished allergen-induced airway hyperresponsiveness, pulmonary eosinophilia, and elevations in serum IgG1 and IgE levels. Anti-B7-2 treatment of OVA-treated mice reduced both total lung IL-4 and IL-5 mRNA and bronchoalveolar lavage fluid IL-4 and IL-5 protein levels, with no significant changes in IFN-gamma message or protein levels. In contrast, treatment with anti-B7-1 mAbs had no effect on allergen-induced airway hyperresponsiveness, IgE production, or cytokine production, however, it significantly suppressed pulmonary eosinophilia. We conclude that B7-2 provides the necessary costimulatory signal required for the development of in vivo allergic responses to inhaled allergen exposure.
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PMID:Development of murine allergic asthma is dependent upon B7-2 costimulation. 955 45

Microglia and astrocytes, two glial cell populations of the central nervous system, present Ag and stimulate T cell proliferation, but it is unclear whether they preferentially activate Th1 or Th2 responses. We have investigated the efficiency of microglia and astrocytes in the presentation of OVA peptide 323-339 or native OVA to Th1 and Th2 cell lines from DO11.10 TCR transgenic mice. Upon stimulation with IFN-gamma, microglia express MHC class II molecules, CD40, and ICAM-1 and efficiently present OVA 323-339, leading to T cell proliferation and production of IL-2 and IFN-gamma by Th1 and of IL-4 by Th2 cells. IFN-gamma-treated astrocytes, which express MHC class II and ICAM-1, present OVA 323-339 less efficiently to Th1 cells but are as efficient as microglia in inducing IL-4 secretion by Th2 cells. However, astrocytes are much less potent than microglia in presenting naturally processed OVA peptide to either T cell subset, indicating inefficient Ag processing. The capacity of astrocytes and microglia to stimulate Th1 and Th2 cells depends on their MHC class II expression and does not involve ICAM-1, B7-1, or B7-2 molecules. However, CD40-CD40L interactions contribute to Th1 activation by microglia. These data suggest that microglia may play a role in the activation of Th1 and Th2 cells, whereas astrocytes would restimulate mainly Th2 responses in the presence of appropriate peptides. This differential capacity of brain APC to restimulate Th1 and Th2 responses may contribute to the reactivation and regulation of local inflammatory processes during infectious and autoimmune diseases.
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PMID:Microglia are more efficient than astrocytes in antigen processing and in Th1 but not Th2 cell activation. 959 Feb 12

The requirement for T cell costimulation at sites of infection and inflammation is unresolved. Herpes stromal keratitis (HSK) is a CD4+ T cell-regulated inflammatory response to herpes simplex virus type 1 infection of the cornea. Our findings suggest that susceptibility to HSK is determined by the microenvironment of the infected cornea. The cornea is normally devoid of Langerhans cells (LC), but these APC are present in the surrounding conjunctiva, and migrate into the cornea following infection. The costimulatory molecule B7-2 was constitutively expressed on LC in conjunctiva, but B7-1 was not detectable until 3 days postinfection. LC were the only cells in the cornea that expressed B7-1 through 7 days postinfection. B7-1 was expressed on some, but not all, migrating LC, suggesting that LC migration and B7-1 expression can be independently regulated. The early LC migration and B7-1 expression was independent of T cells, but T cells were required for the massive accumulation of B7-1+ LC in the cornea at the onset of inflammation. Local inhibition of B7-1 function within the infected cornea prevented HSK. Locally blocking B7-2 function did not reduce HSK incidence, but markedly reduce HSK severity. This is the first direct demonstration that naturally expressed B7 is required within an inflammatory site.
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PMID:B7 costimulatory requirements of T cells at an inflammatory site. 959 Feb 54

In this report we show that activation of APC with an agonist anti-CD40 mAb profoundly alters the behavior of CD4 T cells in vivo. Stimulation of mice with anti-CD40 2 days before, but not 1 day after, administration of superantigen (SAg) enhanced CD4 and CD8 T cell clonal expansion by approximately threefold. Further, CD40 activation also delayed peripheral T cell deletion after activation. Dying, activated T cells were quantitated by detecting extracellular phosphatidylserine with concomitant staining for SAg-reactive T cells using a TCR Vbeta-specific mAb. Upon close examination, it was shown that CD40 activation delayed the death of the activated T cells. Additionally, it was found that enhanced survival of CD4 T cells was equally dependent on APC expression of B7-1 and B7-2. This is in contrast to CD8 T cells, which did not depend as much on B7-1 as B7-2. Thus, CD40 activation indirectly promotes T cell growth and delays the death of SAg-stimulated CD4 T cells in vivo. These data suggest that one way CD40 activation promotes a more robust immune response is by indirectly increasing the production of effector T cells and by keeping them alive for longer periods of time.
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PMID:CD40 activation boosts T cell immunity in vivo by enhancing T cell clonal expansion and delaying peripheral T cell deletion. 997 74

N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.
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PMID:N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition. 1007 97

Microglia share a lineage relationship with bone marrow-derived monocytes/macrophages and dendritic cells, and their inclusion in retinal and brain transplants may function as "passenger leukocytes. " In other solid allografts, passenger leukocytes are the primary sources of immunogenicity, triggering alloimmune rejection. We have conducted a series of in vitro and in vivo studies examining the capacity of microglia cultured from forebrain to activate alloreactive T cells and to induce and elicit alloimmunity. Cultured microglia expressed class II MHC molecules and costimulatory molecules (B7-1, B7-2, and CD40), and they secreted IL-12. Cultured microglia injected s.c. into naive recipients induced allospecific delayed hypersensitivity and elicited delayed hypersensitivity directed at alloantigens. Cultured microglia differed from conventional APCs by secreting significant amounts of mature TGF-beta2, but smaller amounts of IL-12. Moreover, while both cultured microglia and conventional APC stimulated T cell proliferation in vitro, microglia directed the responding T cells toward the Th2 pathway in which IL-4, but not IL-2 and IFN-gamma, was secreted. The abilities of microglia to secrete TGF-beta2, to stimulate alloreactive Th2 cells, and to induce anterior chamber associated immune deviation when injected into the eye of naive allogeneic mice suggest that they are not typical passenger leukocytes. The unique functional properties of cultured microglia may account for the capacity of neonatal retinal tissue transplanted into the eye to alter the systemic alloimmune response in a manner that delays, but does not prevent, graft rejection.
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PMID:T cell immunity induced by allogeneic microglia in relation to neuronal retina transplantation. 1020 85

Although resting B cells as APC are tolerogenic for naive T cells in vivo, we show here that they can provide all the costimulatory signals necessary for naive T cell proliferation in vivo and in vitro. In the absence of an activating signal through the B cell Ag receptor, T cell proliferation after Ag recognition on resting B cells depends on CD40 expression on the B cells, implying that naive T cells use the membrane-bound cytokine, CD40 ligand (CD154), to induce the costimulatory signals that they need. Induction of B7-1 (CD80) and increased or sustained expression of CD44H, ICAM-1 (CD54), and B7-2 (CD86) are dependent on the interaction of CD40 ligand with CD40. Transient expression (12 h) of B7-2 is T cell- and peptide Ag-dependent, but CD40-independent. Only sustained (>/=24 h) expression of B7-2 and perhaps increased expression of ICAM-1 could be shown to be functionally important in this system. T cells cultured with CD40-deficient B cells and peptide remain about as responsive as fresh naive cells upon secondary culture with whole splenic APC. Therefore, B cells, and perhaps other APC, may be tolerogenic not because they fail to provide sufficient costimulation for T cell proliferation, but because they are deficient in some later functions necessary for a productive T cell response.
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PMID:Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40. 1062 11

Mice immunized with peritoneal exudate cells (PEC; used as antigen-presenting cells [APC]) that are pulsed ex vivo with cryptococcal capsular polysaccharide, a glucuronoxylomannan (GXM), exhibit increased survival times and delayed-type hypersensitivity reactions when they are infected with Cryptococcus neoformans. These responses are GXM specific. The present study revealed that GXM-APC immunization enhanced development of anticryptococcal type-1 cytokine responses (interleukin-2 [IL-2] and gamma interferon) in mice infected with C. neoformans. The enhancement was not GXM specific, because immunization with GXM-APC and immunization with APC alone had similar effects. GXM-APC (or APC) immunization caused small increases in the expression of type-2 cytokines (IL-4 and IL-5), but the increases were not always statistically significant. IL-10 levels were not regulated by immunization with GXM-APC or APC. GXM-APC prepared with PEC harvested from mice injected with complete Freund's adjuvant (CFA) enhanced type-1 cytokine responses, while GXM-APC prepared with PEC induced with incomplete Freund's adjuvant were ineffective. The CFA-induced PEC had an activated phenotype characterized by increased numbers of F4/80(+) cells that expressed CD40, B7-1, and B7-2 on their membranes. The immunomodulatory activity of the CFA-induced APC population was not attributed to their production of IL-12 because GXM-APC prepared with peritoneal cells harvested from IL-12 knockout mice or their wild-type counterparts were equally effective in augmenting the type-1 response. Blocking of IL-12 in the recipients of GXM-APC early after APC infusion revealed that early induction of IL-12 secretion was not responsible for the immunomodulatory response elicited by GXM-APC. These data, considered together with previously reported data, reveal that the protective activity of GXM-APC immunization involves both antigen-specific and nonspecific activities of GXM-APC.
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PMID:Regulation of cytokine expression in mice immunized with cryptococcal polysaccharide, a glucuronoxylomannan (GXM), associated with peritoneal antigen-presenting cells (APC): requirements for GXM, APC activation, and interleukin-12. 1094 38


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