Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protection against infection with Mycobacterium tuberculosis is preferentially associated with the development of the T helper 1 subset, IFN-gamma production and a cell-mediated response, rather than with T helper 2 cells, 4 (IL-4) and antibody production. The type of APC interacting with T cells responsive to mycobacterial peptides may influence which of these responses predominates. This investigation focuses on the role of dendritic cells (DC) because they are the most potent APC in both primary and recall immune responses. Our results show that splenic DC-enriched suspensions prepared from C57BL/6 mice and pulsed with either purified protein derivative (PPD) or the immunodominant 19 kDa protein from M. tuberculosis, can activate antigen-primed T cells in vitro, whereas spleen cell suspensions depleted of DC cannot. DC pulsed with PPD or 19 kDa antigen are able to prime naive T cells in vivo. Supernatants collected from cultures containing T cells from mice injected with PPD-pulsed DC and then challenged in vitro with PPD-pulsed DC were found to contain more IL-2 and IFN-gamma than those from control mice which received either DC or PPD alone. No such antigen-specific IFN-gamma response occurred if DC pulsed with 19 kDa were used in place of PPD-pulsed DC. IL-4 was not detected in any of the culture supernatants. We conclude that DC can induce production of cytokines associated with a protective immune response when presenting peptides derived from heterogeneous mycobacterial antigens but not when exposed to the single 19 kDa immunodominant protein.
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PMID:Dendritic cell presentation of PPD and 19 kDa protein of Mycobacterium tuberculosis and emergent T helper cell phenotype. 871 75

We previously reported that human naive CD4 T cells differentiate into effector cells producing type 1 (IL-2, IFN-gamma) and type 2 (IL-4, IL-5, IL-10) cytokines after priming with anti-CD3 mAb presented on irradiated CD32-transfected mouse L fibroblasts, in the absence of exogenous cytokine. Here we first show that the CD32 L fibroblasts act not only by cross-linking anti-CD3 mAb but also by providing a B7-mediated co-stimulation signal which is required for the activation of naive T cells. Using a selected anti-CD3 mAb (64.1) we next demonstrate that colligation of CD3 and CD28 with soluble mAb is sufficient to activate highly purified naive CD4 T cells for proliferation, IL-4 mRNA expression, IL-4 secretion, and maturation into IL-4- and IL-5-producing cells. Finally, we show that the intensity of B7 co-stimulation at priming markedly affects the lymphokine-producing phenotype of primed cells. Indeed, cells primed on CD32-B7 double L transfectants produce much more IL-4 and IL-5 and slightly less IFN-gamma than those primed on CD32 L cells. The enhanced IL-4/IL-5-producing capacity of cells primed on CD32-B7 L fibroblasts may be related to increased IL-4 production during priming. It is suggested that the maturation of naive T cells along the Th2 or Th1 pathway may be regulated by the level of B7 expressed on APC.
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PMID:Maturation of neonatal human CD4 T cells: III. Role of B7 co-stimulation at priming. 874 68

The capacity of APC to stimulate the proliferation of human peripheral blood T cells decreases upon ultraviolet-B (UVB) irradiation. The aim of this study was to investigate whether all T cell subsets are equally sensitive to this reduced APC function. Established human Th1, Th2, and Th0 clones were stimulated with monocytes in a soluble CD3 mAb-mediated assay that is dependent on the presence of APC. Monocytes were exposed to low nonlethal doses of UVB radiation before coculture with T cells. UVB irradiation inhibited the capacity of monocytes to stimulate the proliferation and IFN-gamma production of Th1 cells in a dose-related fashion. In contrast, UVB-treated monocytes induced normal proliferation and IL-4 production in Th2 cells. Stimulation of Th0 cell proliferation by UVB-irradiated monocytes was normal, but a preferential suppression of IFN-gamma production was observed, thus leading to a more Th2-like cytokine response. The loss of Th1 proliferation upon stimulation with UVB-irradiated monocytes could be overcome by rIL-2; however, IFN-gamma production remained suppressed. IFN-gamma production could be completely restored by rIL-12, whereas the addition of IL-1 beta, TNF-alpha, or indomethacin had no such effect, nor did the addition of mAb to CD28, added to compensate for the reduced B7 expression of UVB-irradiated monocytes. Monocytes exposed to UVB radiation exhibited reduced expression of mRNA for the IL-1 2 subunits p35 and p40 and suppressed production of the IL-12 p70 protein. Our results thus indicate that UVB irradiation of APC selectively impairs Th1-like responses, a phenomenon caused by the UVB-induced suppression of monocyte IL-12 production.
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PMID:Reduced IL-12 production by monocytes upon ultraviolet-B irradiation selectively limits activation of T helper-1 cells. 875 9

Two homozygous lines of transgenic NOD/Lt mice expressing MHC class II I-E molecules at quantitatively different levels were utilized to study mechanisms of I-E-mediated diabetes prevention. In line 12, I-E expression on APC at levels comparable with that in BALB/cByJ controls conferred only partial diabetes resistance. In line 5, greater than normal I-E levels on APC correlated with nearly complete resistance. Levels of endogenously encoded I-Ag7 correlated inversely with transgene-induced I-E expression. T cell transfer experiments into NOD/severe combined immunodeficient mice demonstrated the presence of pathogenic T cells in I-E+ donors, and that continuous expression of I-E on hemopoietically derived APC was required to block their pathogenic function. T cells from transgenic and nontransgenic NOD/Lt mice primed in vivo against the beta cell autoantigen 65-kDa isoform of glutamic acid decarboxylase (GAD65) and two peptides derived from this protein proliferated when restimulated in vitro. However, reverse-transcription PCR and ELISA measurements of cytokine mRNA and protein levels showed that the GAD65-reactive T cells from both line 5 and line 12 mice produced higher levels of IL-4 and lower levels of IFN-gamma than similar T cells from standard NOD/Lt mice. Thus, the inverse relationship between I-E and I-Ag7 expression was associated with qualitative differences in T cell responses to putative beta cell autoantigens. Collectively, these data indicate quantitative increases in I-E expression on APC may block insulin-dependent diabetes mellitus by altering the balance of cytokines produced by beta cell autoreactive T cells.
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PMID:Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. 875 36

Murine epidermis contains two leukocyte populations: Langerhans cells (LC), which are APC of dendritic cell (DC) lineage, and dendritic epidermal T cells (DETC), which are members of the tissue-type gamma delta T cell family. Despite close physical approximation in vivo, the extent to which LC and DETC affect each other's function has remained unknown. We addressed this question using the long term DC line XS52 and the gamma delta T cell line 7-17, both of which were established from mouse epidermis, and both of which retain important features of the resident populations from which they were derived. XS52 DC proliferated maximally when cocultured with gamma-irradiated 7-17 DETC. They also proliferated in response to culture supernatants collected from anti-CD3- or Con A-activated 7-17 DETC, but not from nonstimulated DETC. In both systems, DETC-induced XS52 DC growth was inhibited partially (up to 70%) by Abs against granulocyte/macrophage CSF (GM-CSF) or CD115 (CSF-1 receptor) and nearly completely (up to 90%) by both together. Among 28 tested cytokines, only GM-CSF, CSF-1, IL-4, and IL-13 promoted XS52 DC growth significantly. Anti-IL-4 failed to inhibit DETC-induced XS52 cell growth, and IL-4 was not detectable in DETC supernatants. Thus, we conclude that GM-CSF and CSF-1 (and perhaps IL-13) account for the DC growth-promoting activity secreted by DETC. These results suggest that during coculture, XS52 DC activate 7-17 DETC to secrete both GM-CSF and CSF-1. In fact, when cultured with XS52 DC, 7-17 DETC also elevated their expression of the gamma c receptor and acquired proliferative responsiveness to their own growth factor IL-15. We propose that LC and DETC in situ may interact with each other in a similar manner, thereby regulating their residence and function.
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PMID:Cytokine-mediated communication between dendritic epidermal T cells and Langerhans cells. In vitro studies using cell lines. 875 35

The Th1 subset of CD4+ T cells mediate both delayed-type hypersensitivity (DTH) responses and experimental allergic encephalomyelitis (EAE). Th1 cells are induced by immunization of young adult female and older (> or = 10 wk of age) male SJL mice. By contrast, young adult (< or = 8 wk of age) male mice are characterized by the inability of immunization to induce either a DTH response or EAE, demonstrating a clear sex and age dependence to these Th1-mediated responses in SJL mice. T cell activation in age-matched female and male SJL mice was compared to understand the mechanism(s) of these differential responses. Here, we report that immunization of DTH responder female mice primes for Ag-specific secretion of IFN-gamma but not IL-4 and IL-10. In contrast, immunization of DTH nonresponder male mice primes Ag-specific T cells that secrete IL-4 and IL-10, but not IFN-gamma. Depletion of either IL-4 or IL-10 recovers DTH responsiveness in young adult male mice, demonstrating expansion of Th1 cells in these mice when Th2 cytokines are suppressed. The age- and sex-dependent inability to prime Th1 cells in young male mice is due to the functional absence of a macrophage APC population defined by co-expression of Mac-1 and Mac-3. To determine whether Th2 cytokines directly affect the APC's ability to support the priming of Th1 cells, Mac-3+ APC isolated from naive young male donors, which had been depleted of either IL-4 or IL-10, were transferred into DTH nonresponder males. Induction of DTH responses in these recipients demonstrates that in vivo suppression of Th2 cytokines enables the male-derived Mac-3+ APC to support priming of Th1 responses. These data indicate that, in addition to their regulatory roles in controlling preferential T cell subset expansion, exposure of APC to cytokines in vivo before the initial encounter with Ag may regulate induction of CD4+ T cell subsets.
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PMID:Exposure to T helper 2 cytokines in vivo before encounter with antigen selects for T helper subsets via alterations in antigen-presenting cell function. 881 86

IL-4 promotes the development of type 2 CD8+ T cells. In mice infected with the helminth Schistosoma mansoni, the Th response is overtly Th2-like, creating an environment rich in IL-4. Consequently, we examined whether CD8+ subset development in schistosome-infected mice is biased in a type 2 direction; this is of interest because CD8+ cells have been proposed to play an immunoregulatory role during schistosomiasis. Contrary to expectation, our data indicate that the CD8+ cell response in infected mice is strongly type 1-like. Thus, infection with S. mansoni leads to the development of concurrent Th2 and type 1 CD8+ cell responses. Cytokine production by type 1 CD8+ cells is dependent upon help from CD4+ cells; this helper activity can be substituted by exogenous IL-2 or IL-4. Since Th cells from infected mice make little IL-2 but large amounts of IL-4, we propose that IL-4 is likely to be the physiologic mediator of help in infected animals, a view supported by the ability of mAbs against IL-4R and IL-4 to reduce IFN-gamma production by splenocytes in vitro. CD8+ cells from infected mice are able to produce IFN-gamma in response to schistosome Ag presented by bone marrow-derived APC. A regulatory role for the CD8+ cells is implied by the observation that CD8+ cell-depleted splenocytes from infected mice exhibit increased proliferative responses and IL-4 production in response to mAb anti-CD3. These findings suggest that in mice infected with schistosomes there exists a regulatory pathway in which type 1 CD8+ cells, under the control of IL-4, dampen immunopathologic type 2 responses.
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PMID:Type 1 CD8+ T cell responses during infection with the helminth Schistosoma mansoni. 881 14

T helper cells, which recognize allopeptides processed and presented by self APC, contribute to the generation of both cellular and humoral immune responses against allogeneic transplants. We have explored the hypothesis that the indirect T cell recognition pathway is initiated by soluble MHC antigens and that it can be suppressed by high doses of synthetic peptides corresponding to the dominant alloepitope. T cells from a DR11/7 responder were immunized in vitro with recombinant HLA-DR4 (rDR4). Experiments using partially overlapping synthetic peptides showed that the resulting T cell line (TCL) recognized a single dominant epitope mapping within residues 69-88 of the first domain of the DR4 molecule. In vitro immunization with synthetic allopeptides corresponding to other polymorphic regions, were unable to elicit T cell reactivity against rDR4, although at least one of these peptides (corresponding to residues 13-27) was immunogenic, behaving like a cryptic epitope. The rDR4-specific TCL expressed a limited TCR repertoire and provided help to autologous B cells for the production of specific antibodies. The T cell blastogenic response as well as the transcription and secretion of IL-4 (but not IL-2) was efficiently suppressed by high doses of the dominant allopeptide. These findings support the concept that selective immunointervention of indirect allorecognition can be achieved by use of high doses of antigen or TCR vaccination, as proposed for autoimmune diseases.
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PMID:Suppression of the indirect pathway of T cell reactivity by high doses of allopeptide. 882 75

We have investigated an improved method for generating sizable numbers of mature dendritic cells from nonproliferating progenitors in human blood. The procedure uses 1% human plasma in the place of 10% fetal calf serum and involves two steps. The first step or 'priming' phase is a 6-7 day culture of T cell depleted mononuclear cells in medium supplemented with GM-CSF and IL-4. The second step or 'differentiation' phase requires the exposure to macrophage conditioned medium. This medium cannot be replaced by several known cytokines such as TNF-alpha, IL-1, IL-6, IL-12 and IL-15, and cannot be inhibited with neutralizing antibodies to IL-1, TNF-alpha, IL-6 or IL-12 alone, or in combination. Using this two-step approach, we obtain substantial yields. About 1-3 x 10(6) mature dendritic cells are generated from 40 ml of blood vs. < 0.1 x 10(6) from noncytokine treated blood. The dendritic cells derive from progenitors found primarily in a radioresistant population of CD14+ and adherent blood mononuclear cells and have all the features of mature cells. They include a stellate cell shape, nonadherence to plastic, and very strong T cell stimulatory activity. Strong APC function was evident for both the proliferation of allogeneic T cells in the MLR, and the generation by syngeneic T cells of class I restricted, CTL responses to influenza virus. A panel of dendritic cell restricted markers is also expressed, including CD83, p55, and perinuclear CD68. All of these dendritic cell properties are retained for at least 3 days when the cytokines are removed, suggesting that these populations are stable and terminally differentiated. We suggest that these cells will be effective in vivo as adjuvants for active immunotherapy.
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PMID:Improved methods for the generation of dendritic cells from nonproliferating progenitors in human blood. 884 51

We used naive CD4 cells and in vitro-derived Th1 and Th2 effectors from TCR transgenic mice to investigate the requirements of these subsets for TCR signaling and interactions with accessory molecules. Peptide Ag and immobilized anti-CD3 were used to provide different TCR signals. Anti-CD28 Ab or a panel of class II+ fibroblasts, expressing no accessory molecules or expressing intracellular adhesion molecule-1, B7-1, or both molecules, were used as APC or accessory cells (AC). An efficient naive T cell response required a strong TCR signal (high dose anti-CD3 or peptide) and high levels of multiple synergizing costimulatory signals, while effector cells responded efficiently to anti-CD3 alone. Addition of AC only slightly augmented the effector response. Effectors responded to lower doses of peptide than naive cells. However, when peptide-pulsed APC were used to stimulate effectors, requirements varied with the cytokine measured. The production of IL-4 did not require accessory molecules on APC. IL-2 production required interacting APC to express accessory molecules, but was little augmented by AC not presenting Ag, suggesting a requirement for noncostimulatory interactions. Proliferation of effectors closely paralleled IL-2 production. Production of IFN-gamma was intermediate in dependence on accessory molecules, and production of IL-5 was nearly as dependent as IL-2. These results establish major differences between the induction of naive and effector responses and document differential requirements for the induction of distinct cytokines, indicating that different cytokines may be produced depending on the context of effector restimulation.
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PMID:Naive and effector CD4 T cells differ in their requirements for T cell receptor versus costimulatory signals. 2340 Aug 44


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