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

Presentation of Ag to type I CD4+ T cell clones by chemically fixed APC results in the induction of a long-lasting state of proliferative unresponsiveness in the T cell. Ag-specific TCR interactions do occur during this stimulation, as Ag- and Ia molecule-dependent increases in intracellular calcium free ion concentration can be demonstrated, yet free inositol phosphate generation is low and neither IL-2 synthesis nor proliferation occur. The addition of normal allogeneic accessory cells during this stimulation can restore the T cell proliferative response, as well as prevent the induction of unresponsiveness, thus defining an accessory cell-dependent costimulatory activity necessary for proliferation. We have now examined the biochemical effects of this costimulatory activity on early T cell activation. Normal accessory cell costimulatory activity was found to be incapable of augmenting the generation of free inositol phosphate in response to either fixed APC plus Ag or Con A alone. Furthermore, protein kinase C-dependent CD3 gamma-chain phosphorylation occurred in response to either fixed APC plus Ag or Con A alone, and the addition of normal accessory cells had no effect on the level of this phosphorylation. Finally, minimal CD3 zeta-chain tyrosine phosphorylation occurred during the induction of unresponsiveness with Ag and fixed APC alone and this also was not affected by the costimulatory activity. Our results demonstrate that T cell Ag receptor-mediated increases in intracellular calcium free ion concentration and protein kinase C activation occur independently of an accessory cell-derived costimulatory signal. In the absence of this costimulatory signal, these two intracellular second messengers are insufficient to induce a maximal proliferative response and in fact lead to a state of unresponsiveness.
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PMID:An accessory cell-derived costimulatory signal acts independently of protein kinase C activation to allow T cell proliferation and prevent the induction of unresponsiveness. 252 63

A cytokine synthesis inhibitory factor (CSIF) is secreted by Th2 clones in response to Con A or antigen stimulation, but is absent in supernatants from Con A-induced Th1 clones. CSIF can inhibit the production of IL-2, IL-3, lymphotoxin (LT)/TNF, IFN-gamma, and granulocyte-macrophage CSF (GM-CSF) by Th1 cells responding to antigen and APC, but Th2 cytokine synthesis is not significantly affected. Transforming growth factor beta (TGF-beta) also inhibits IFN-gamma production, although less effectively than CSIF, whereas IL-2 and IL-4 partially antagonize the activity of CSIF. CSIF inhibition of cytokine synthesis is not complete, since early cytokine synthesis (before 8 h) is not significantly affected, whereas later synthesis is strongly inhibited. In the presence of CSIF, IFN-gamma mRNA levels are reduced slightly at 8, and strongly at 12 h after stimulation. Inhibition of cytokine expression by CSIF is not due to a general reduction in Th1 cell viability, since actin mRNA levels were not reduced, and proliferation of antigen-stimulated cells in response to IL-2, was unaffected. Biochemical characterization, mAbs, and recombinant or purified cytokines showed that CSIF is distinct from IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IFN-gamma, GM-CSF, TGF-beta, TNF, LT, and P40. The potential role of CSIF in crossregulation of Th1 and Th2 responses is discussed.
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PMID:Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. 253 Nov 94

Four regulatory phenomena appear to regulate differentially the activation of TH1, TH2, and CTL clones. First, IFN-gamma selectively inhibits proliferation of TH2 but not TH1 cells; lymphokine production by TH2 cells is not affected by IFN-gamma. In addition, when fresh OVA-specific HTL clones are derived in the presence of rIL-2 TH2 cells are preferentially obtained, whereas TH1 cells predominate if cloning is performed in rIL-2 plus rIFN-gamma. These results suggest that the presence of IFN-gamma during the course of an immune response would result in the preferential expansion of HTL of the TH1 phenotype. Proliferation of CTL clones is not influenced by IFN-gamma. Second, different APC populations appear to differentially activate TH1 and TH2 clones. Purified splenic B cells stimulate optimal proliferation of TH2 but not TH1 cells, whereas macrophage/dendritic cells appear to stimulate optimal proliferation of TH1 but not TH2 cells. Since both APC types stimulate lymphokine production by each of the HTL subsets, these results suggest the existence of TH1- and TH2-specific cofactors for growth. Third, high doses of immobilized anti-CD3 mAb inhibit IL-2-dependent proliferation of TH1 but not TH2 clones. Since this effect appears to require calcium, this observation suggests that TCR-mediated signalling events might differ between the two HTL subsets. Indeed, little or no increase in [Ca++]i can be detected in TH2 clones stimulated with Con-A, while such an increase is easily discernible in TH1 cells. Although high concentrations of immobilized anti-CD3 mAb inhibit IL-2-dependent proliferation of CTL clones, proliferation of these cells in response to immobilized anti-CD3 alone reaches a plateau. Since activation with anti-CD3 is thought to mimic antigenic stimulation, these results suggest that antigen concentration may play a role in determining which predominant T-cell types proliferate in a particular immunological situation. Fourth, pretreatment of TH1 cells, but not TH2 cells or CTL, with IL-2 results in decreased lymphokine production and proliferation in response to subsequent stimulation via the TCR. This antigen-responsive state appears to involve a defect in calcium-dependent signalling, providing additional evidence for different signalling mechanisms in TH1 and TH2 clones.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of T-cell activation: differences among T-cell subsets. 253 16

Previous evidence from several laboratories suggests that CD8+ T suppressor cells may be important regulatory elements governing specific unresponsiveness of lepromatous lepromatous leprosy patients to M.leprae. To analyse the mechanism of suppression, CD8+ Ts clones were established from lesions and peripheral blood of lepromatous patients and tested for ability to suppress antigen-responsive CD4+. Th clones or PBL. Suppression required induction by specific M.leprae antigen, but was effected in an antigen-non-specific fashion. The Ts clones failed to exhibit cytotoxicity of four antigen-exposed MHC-matched target cells: (i) an ori-SV40 transformed macrophage line; (ii) EBV transformed B cell lines; (iii) primary macrophages; and (iv) M.leprae responsive CD4+ cells. The possibility that Ts clones induce functional inactivation of CD4+ clones in vitro was investigated. M.leprae-responsive CD4+ clones were preincubated with Ts CD8+ clones, APC, and antigen for 16 h, after which the CD8+ cells were removed. The CD4+ clones with M.leprae and APC remained unresponsive to restimulation with APC and antigen for at least 10 days, although they responded to IL-2. Addition of IL-2 to the pre- or post-incubation cultures neither prevented the induction of unresponsiveness, nor reversed it. Earlier models of tolerance have suggested that receptor occupancy in the absence of second signals induces tolerance in B and T cells. Under conditions in which antigen responses of Th clones were HLA-DR-restricted, the Ts clones were able to suppress the response of DR mismatched Th clones. Thus, the effect of the Ts cells, like mechanisms requiring antigen presentation without a second signal, appears to be induction of clonal anergy in Th cells, perhaps by a novel mechanism.
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PMID:On the mechanism of human T cell suppression. 253 60

This paper describes an adjuvant-free immunization regimen that results in the priming of T cells but not B cells. B10.A mice were primed s.c. with syngeneic spleen cells that had been pulsed with the peptide 81-104 derived from pigeon cytochrome c. The T cell response was measured by using a sensitive limiting dilution assay that measures lymphokine production. The precursor frequency of Ag-specific cells found in these mice was indistinguishable from the frequency found in mice primed in the footpads with 81-104 in CFA. A striking difference in antibody induction was found, however, when these two immunization regimens were compared. Mice primed with 81-104 in CFA developed significant serum antibody responses against the peptide, whereas mice primed with Ag-pulsed spleen cells produced no detectable anti-peptide antibodies. This lack of antibody did not result from detectable differences in the T cells that were primed: no differences were seen in IL-2 and IL-4 production or in the ability to provide help to B cells in vitro. In vitro stimulation with LPS suggested that the B cells were not primed by the Ag-pulsed spleen cells. The B cells were not tolerized, however, because boosting the mice with Ag in CFA resulted in the induction of an antibody response. The failure to induce an antibody response by priming with Ag-pulsed spleen cells was not caused by the site of immunization or the total amount of Ag used for priming. The critical variable may be the introduction of the Ag on the surface of an APC; in this form, B cell Ag recognition was apparently inefficient, whereas T cell Ag recognition was optimal.
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PMID:In vivo priming of helper T cells in the absence of B cell activation. 255 72

We have studied the production of IL-2, IL-4 and IFN-gamma by a panel of CD4+ clones produced in our laboratory. The clones were classified as TH1 and TH2 because of their ability to secrete IL-2 or IL-4, respectively, following stimulation with APC + Ag and by their characteristic proliferative responses to exogenous IL-2 or IL-4. Some of the TH2 clones, all of which happened to be autoreactive, produced IL-2 and one of these, as well as one antigen-reactive TH2 clone, also secreted IFN-gamma following stimulation with immobilized anti-CD3 mAb. IL-2 production by TH2 cells required higher concentrations of anti-CD3 mAb than IL-4 production. Thus, the TH2 clones seem to be heterogeneous. We designate the IL-2/IL-4 secretors as TH2B and those making IL-4 as TH2A clones.
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PMID:Production of IL-2 and IFN by TH2 clones. 257 41

To study the biochemistry of processing of a soluble protein Ag by an APC, we investigated how 125I-labeled human insulin (HI) is processed in situ by TA3 mouse hybridoma B cells. Fractionation of TA3 cells into their extracellular, plasma membrane-associated and intracellular compartments coupled with the use of HPLC enabled us to analyze several peptides derived from each compartment. One HI peptide found in all three compartments is composed of residues A1-A14 disulfide-linked to B7-B26 (A1-A14/B7-B26). The presence of this peptide in the extracellular compartment likely resulted from digestion of HI by an enzyme(s) released from the APC. Extracellular processing of radiolabeled HI was inhibited completely by unlabeled HI and N-ethylmaleimide, an inhibitor of a previously described insulin-specific protease, partially by lysozyme but not by BSA or OVA. This suggests that the enzyme involved in the extracellular processing of insulin is relatively insulin-specific and gives rise to the A1-A14/B7-B26 peptide. The processing of HI both at the plasma membrane and intracellularly was inhibited by chloroquine, monensin, and NH4Cl, suggesting that both intracellular pH changes and endocytic and exocytic events may be required for these compartments to process insulin. Kinetic analyses revealed that the processing of insulin into the A1-A14/B7-B26 peptide is first detected at the plasma membrane then intracellularly and finally in the extracellular compartment. This unlabeled A1-A14/B7-B26 peptide was purified from the extracellular compartment of TA3 APC by HPLC; when presented by TA3 APC this peptide effectively stimulated pork insulin (PI/I-Ad) specific Th cells to secrete IL-2. These data, taken together with the identification of another processed insulin peptide, A7-A11/B7-B26, have enabled us to elucidate the first steps in the biochemical pathway(s) of processing of insulin as an Ag in a B cell APC.
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PMID:Processing and presentation of insulin. II. Evidence for intracellular, plasma membrane-associated and extracellular degradation of human insulin by antigen-presenting B cells. 265 61

During the past decade, much has been learned about the pathophysiology of ACH--yet much remains to be determined. Although LC, IL-1, IL-2, IFN-gamma, and the T effector circuits have been extensively studied, it is still not clear whether it is LC- or keratinocyte-derived IL-1 that is crucial in ACH, whether IL-1 acts primarily on T-cells or the APC, whether other cytokines are involved in the circuit (TNF, KTGF?), the exact relationships between T effector, T memory, and other T helper cells, what the functions of mast cells and basophils are in the allergic reaction, and how the regulatory circuits (including prostaglandins and eicosanoids) affect the outcome of ACH. The mechanism of suppression remains even less well understood despite the potential application of this knowledge to the treatment of diseases caused by Type IV hypersensitivity. A better understanding of the ACH mechanism will lead not only to more sophisticated ACH treatment, but also to a better understanding of the cell-mediated events of cutaneous viral replication, organ transplantation, and tumor growth.
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PMID:The pathophysiology of allergic contact hypersensitivity. 269 Oct 41

Cholera toxin (CT) is a potent oral immunogen that also acts as a strong mucosal adjuvant for immune responses to related as well as unrelated Ag. To elucidate the immunomodulating effects of CT at the cellular level we have examined interactions of CT with APC and with B and T lymphocytes in vitro. CT markedly stimulated the production of IL-1 from APC (mouse peritoneal macrophages or macrophage cell line P388D1) but did not induce Ia-Ag and had marginal, if any, effect in potentiating Ia Ag expression stimulated by rIFN-gamma on these cells. CT had differential effect on T cell proliferation in vitro, usually strongly inhibitory but on Con A-stimulated spleen cells during prolonged (greater than or equal to 5 days) culture or when added on day 4 or later to these cultures up to a two- to three-fold enhancement of proliferation was seen. CT-induced inhibition of T cell proliferation was associated with decreased production of IL-2 and anergy to exogenously added IL-2 despite apparently normal expression of IL-2R. Similar to what was found with T cells LPS-stimulated spleen B cells demonstrated both inhibition and enhancement of proliferation in the presence of CT: in high concentrations (greater than or equal to 10(-8) M) and early in culture (day 3) CT had a strong inhibitory effect on the proliferation of B cells, whereas later (day 6) and/or at lower CT concentrations (10(-9) to 10(-11) M) the proliferation was increased up to 10-fold. The net effect of CT treatment on Ig-production by LPS-stimulated spleen B cells was seen as an enhanced level of IgA and IgG but not IgM in culture supernatants. The differential effects of CT on the cells of the immune system observed in vitro may, singly or in combination, explain the immunostimulatory function of CT.
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PMID:Cellular basis of immunomodulation by cholera toxin in vitro with possible association to the adjuvant function in vivo. 278 24

Experiments were conducted in an effort to determine the ability of B and T lymphocytes to serve as APC for the activation of HSV-primed splenic T cells to become class I-restricted, HSV-specific CTL. The results showed that both freshly isolated splenic B cells as well as LPS and dextran sulfate (L/D)-activated B cells were effective at stimulating the generation of CTL during a 5-day in vitro culture. There was no requirement for the addition of exogenous IL-2 to the culture and, since murine B cells do not appear to express either membrane or secreted IL-1, this lymphokine appears to either not be required for the activation of virus-specific CTL or to be provided by the T cells themselves. When normal B cells were separated into fractions enriched for resting vs activated cells and then tested for their ability to stimulate the generation of HSV-specific CTL, it was found that while the activated B cells were quite effective at stimulating the generation of CTL, resting B cells were ineffective at carrying out this function. In contrast to normal B cells, normal T cells were unable to act as APC. However, Con A-activated T lymphoblasts were equivalent to L/D B cells in their ability to mediate the generation of CTL activity. L/D B cells that had been pulsed with HSV and then incubated at 37 degrees C for greater than 1 h could be fixed with paraformaldehyde and were still able to function as APC. The finding that L/D B cells, that had been fixed at 1 h or less after exposure to HSV, were unable to function as APC suggested that either active Ag "processing" steps may be required for the presentation of Ag in the context of class I molecules or that there is a requirement for the synthesis of viral protein Ag before presentation.
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PMID:Studies on the capacity of B cells as well as T cells to serve as accessory cells for the activation of herpes simplex virus-specific cytolytic T cells. 283 Dec 77


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