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)

Because UV-induced epidermal macrophages (UV-Mph) preferentially activate CD4+ T suppressor-inducer cells and induce tolerance, we hypothesized that they differentially up-regulate T cell early activation genes compared with constitutive epidermal APC, Langerhans cells. We used epidermal cells from UV-exposed (UV-EC) and control (C-EC) human skin to stimulate allogeneic CD4+ T lymphocytes. Reverse transcriptase-PCR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induced 10(3)- to 10(6)-fold increases in IL-2 mRNA. However, while T cells stimulated by C-EC for 48 h showed a greater than 10(3)-fold increase in IL-2R alpha mRNA, those stimulated by UV-EC did not (n = 5, p = 0.004). Flow cytometry demonstrated that 4.1 +/- 2.3% of unstimulated CD4+ lymphocytes expressed cell surface IL-2R alpha, which increased to 15.7 +/- 1.8% upon stimulation by C-EC for 48 h, but stimulation by UV-EC failed to increase the IL-2R alpha+ population (n = 3, p = 0.038). The addition of neutralizing anti-TGF-beta Abs to UV-EC-stimulated cultures restored CD4+ cell surface IL-2R alpha expression to 12.9 +/- 0.2%. CD4+ T cell activation by UV-Mph is distinct from previously described models of tolerance such as Th2 activation (IFN-gamma mRNA was induced and IL-4 mRNA was not) and Th1 anergy (IL-2 mRNA levels induced by UV-EC and C-EC were similar). Furthermore, costimulatory signals were provided by UV-Mph; CTLA4-Ig and LFA-3-Ig fusion proteins and Abs to CD2, LFA-3, LFA-1, and ICAM-1 inhibited UV-Mph-induced T cell proliferation. Thus, the altered immune outcome induced by UV-Mph (tolerization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4+ T cell early activation gene expression characterized by TGF-beta-dependent deficient IL-2R alpha expression.
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PMID:Suppressor T cell-activating macrophages in ultraviolet-irradiated human skin induce a novel, TGF-beta-dependent form of T cell activation characterized by deficient IL-2r alpha expression. 749 43

In addition to the interaction between the TCR and the MHC/Ag complex on the APC, optimal T cell activation also requires interaction between adhesion molecules on the APC and their ligands on T cells. We determined the presence of adhesion molecules on human epidermal Langerhans cells (LC) and their role in Ag-specific T cell activation. Freshly isolated LC did not display ICAM-1 (CD54), ICAM-2, LFA-1 (CD11a), and LFA-3 (CD58), as detected by double-color FACS analysis, using HLA-DR expression for LC identification. Upon culture, LC clearly expressed ICAM-1 and LFA-3, both already detectable after 1 day, reaching a plateau at day 2. ICAM-2 and LFA-1 were undetectable on cultured LC and attempts to induce this expression by different culture conditions remained unsuccessful. mAb against ICAM-1, LFA-1, LFA-3, and CD2, continuously present during culture, inhibited the T cell proliferative response to Candida albicans presented by cultured LC. Pretreatment of LC and/or T cells with mAb indicated that anti-ICAM-1 and anti-LFA-3 inhibited at the LC level, whereas anti-LFA-1 and anti-CD2 inhibited at the T cell level. The mAb-induced inhibition was dose-dependent, but a total blockade of the response was never achieved. Time-course observations revealed that ICAM-1 and LFA-3 on LC only functioned during the initiation phase of T cell activation. Our study demonstrates that both ICAM-1 and LFA-3 on LC considerably contribute to the generation of a T cell response. The high expression of these accessory molecules enable LC, at least in part, to perform their powerful Ag-presenting function.
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PMID:Function of adhesion molecules lymphocyte function-associated antigen-3 and intercellular adhesion molecule-1 on human epidermal Langerhans cells in antigen-specific T cell activation. 751 46

Dendritic cells (DC) are potent APCs, able to induce efficiently primary T cell-mediated responses to foreign Ags. To assess the efficiency of DC, as compared with other APC types, in the in vivo presentation of self-Ags to CD4+ T cells, we analyzed processing and presentation to class II-restricted T cells of endogenous naturally processed self-epitopes constitutively expressed by mouse APC. Mouse beta 2-microglobulin (m beta 2-m) peptides corresponding to residues 26-39 and 24-36 are constitutively presented, in mice expressing m beta 2-m, by I-Ad and I-Ed molecules respectively, as demonstrated by activation of m beta 2-m-specific T cell hybridomas generated in BALB/c beta 2-m-deficient mice. These dominant, naturally processed self-epitopes of m beta 2-m are presented by APC from a variety of tissues, including the thymus. To analyze the relative efficiency of different APC populations in the presentation of self-beta 2-m, the ability of purified DC, macrophages, and large or small B cells to stimulate m beta 2-m-specific T cell hybridomas was tested. Naturally processed self-m beta 2-m epitopes are constitutively presented to T cells by any class II-positive APC tested, but with highest efficiency by splenic and thymic DC, followed by macrophages, large B cells, and small B cells. This hierarchy of self-beta 2-m presentation does not depend on differential processing capacity of these APC populations, and it correlates with expression of CTLA-4 ligands and ICAM-1 molecules, rather than with expression of class II molecules.
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PMID:Dendritic cells are the most efficient in presenting endogenous naturally processed self-epitopes to class II-restricted T cells. 752 78

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

Since Pam 212 cells express low levels of class I major histocompatibility (MHC) antigens, we tested their ability to present alloantigens or minor histocompatibility (mH)/minor lymphocyte stimulatory (mls) antigens in disparate hosts. After subcutaneous injection, Pam 212 cells grew progressive tumors in normal BALB/c mice but were rejected rapidly by naive C3H mice (3 weeks) and slowly by DBA/2 mice (8 weeks). Pam 212 cells (high or low class I MHC expression) induced a strong primary MLR in DBA/2 T cells, but a weak BALB/c T-cell response. In contrast, splenic APC (BALB/c) did not induce an MLR, suggesting that Pam 212 cells represented mH antigens to naive DBA/2 T cells. This MLR was blocked by anti-TCR alpha/beta, anti-class II, and anti-CD4 monoclonal antibodies, but was independent of ICAM-1 and B7. Repeated immunization using IFN-gamma-treated Pam 212 cells induced anti-Pam 212 CTL in DBA/2 mice but not in BALB/c mice. DBA/2 T-cell responses did not appear to be mls (MMTV superantigen)-specific, because Pam 212 cells did not express MMTV mRNA detectable by RT-PCR. Pam 212 cells presented non-lymphoid-associated mH antigens that served as potent stimuli for tumor rejection in mH/mls-disparate hosts, which is similar to tumor rejection mediated by MHC alloantigens.
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PMID:Minor histocompatibility antigen-dependent rejection of Pam 212 epidermoid carcinoma by DBA/2 mice. 754 74

The B7 molecule is expressed by APC that can costimulate T cells by binding the T cell surface receptors CD28 and CTLA-4. The human epidermal Langerhans cell (LC) is one of the most potent APC, yet B7 expression by this cell type has not previously been assessed. We used a CTLA4-Ig fusion protein that binds B7 with high avidity to probe cell surface expression of B7 by cultured and noncultured LC. LC cultured for 1 or more days were specifically stained with biotinylated CTLA4-Ig and fluorescent streptavidin. In contrast, binding of CTLA4-Ig to freshly isolated LC was not detected. The cell surface distributions of B7 and of HLA-DR on cultured LC differed, as CTLA4-Ig binding was localized to discrete foci, whereas anti-DR mAb uniformly stained the LC plasma membrane. Analyses of epidermal cell (EC) mRNA indicated that the B7 gene is expressed by these cells. Thus, B7 gene probes specifically hybridized to polymerase chain reaction-amplified B7 mRNA isolated from cultured and noncultured EC. As LC are the only normal epidermal cell type that induces proliferation of allogeneic T cells, the role of B7 in this LC function was studied by coculturing highly purified resting CD4+ T cells and allogeneic EC in the presence of CTLA4-Ig, anti-CD54 (RR/1, anti-intercellular adhesion molecule-1) mAb, or both. CTLA4-Ig and RR/1 each inhibited CD4+ T cell responses to freshly isolated allogeneic EC, and cooperative inhibition of more than 90% was observed in cultures treated with both CTLA4-Ig and RR/1 at 5 micrograms/ml. CTLA4-Ig inhibited stimulation by either fresh EC or cultured EC, suggesting that the increased potency of cultured LC vs noncultured LC may reflect the time needed for noncultured LC to express cell surface B7 in vitro. These studies indicate that B7 is expressed on the cell surface of cultured LC, and that LC B7 costimulates the proliferation of resting allogeneic CD4+ T cells.
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PMID:Expression and function of B7 on human epidermal Langerhans cells. 767 25

Optimal stimulation of CD4+ T cells in an immune response requires not only signals transduced via the CD3/TCR complex but also costimulatory signals delivered as a consequence of interactions between T-cell surface-associated costimulatory R and their counter-R on APC. CD28 plays a crucial role as a dominant costimulatory R during the induction of CD4+ T-cell proliferation by interacting with counter-R B7 on APC to sustain IL-2 production. The absence of CD28-mediated costimulation has been postulated to result in T-cell anergy or unresponsiveness. The costimulatory effects of CD28 can be generated with its natural counter-R B7 or mAb directed at CD28. Using soluble C gamma 1 chimeras of B7, ICAM-1, and VCAM-1, we have recently shown that B7 costimulates TCR-dependent proliferation of Ag-primed CD4+ T cells more efficiently than that of resting nonactivated CD4+ T cells. In contrast, proliferation of resting CD4+ T cells can be efficiently costimulated by either ICAM-1 or VCAM-1 via interactions with their R CD11a/CD18 (LFA-1/beta 2 integrin) and CD29/CD49d (VLA-4/beta 1 integrin), respectively. TCR-directed preactivation of resting CD4+ T cells with ICAM-1 can induce increased responsiveness to B7 costimulation. In this study, we show that prior TCR-directed activation of resting CD4+ T cells with VCAM-1 induced increased responsiveness to B7 costimulation. VCAM-1 also synergized with B7 to bring about supraoptimal proliferation of CD4+ T cells. In addition, costimulation of resting T cells with VCAM-1 significantly increased not only surface expression of CD28 but also CD28-mediated mobilization of intracellular free [Ca2+]i. Similar activation of T cells with fibronectin also resulted in increased B7 responsiveness, suggesting the involvement of VLA-4 molecule. VCAM-1 costimulation induced hyperresponsiveness to B7 costimulation in both CD18+ (normal) and CD18- (leukocyte adhesion deficient) T cells. Thus, VCAM-1 may play an important costimulatory role during the activation of resting T cells and, by augmenting responsiveness to B7, facilitate optimal development of immunological memory in addition to various regulatory and effector functions.
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PMID:Costimulation via vascular cell adhesion molecule-1 induces in T cells increased responsiveness to the CD28 counter-receptor B7. 768 25

The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.
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PMID:Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. 768 12

CD4+ Th cell infiltration into the brain and the activation by cellular elements of the central nervous system (CNS) are thought to be important steps in the initiation of CNS autoimmune diseases. T cell activation requires Ag-specific stimulation and additional costimulatory signals provided by the APC. Here we describe how murine brain microvessel endothelial (En) cells and smooth muscle/pericytes (SM/P) selectively induce the Ag-specific activation of different Th1 and Th2 CD4+ T cell clones. Th1 and Th2 cell clones were used that were specific for the same peptide Ag in the context of the same class II allotype. SM/P preferentially activated Th1 cell clones, whereas En cells activated Th2 cell clones better, as reflected by cell proliferation and production of IL-2 by SM/P-activated Th1 clones and IL-4 by Th2 clones. There was no difference in the level of expression of CD4, CD2, or LFA-1 molecules between these Th cell clones, and anti-CD4, CD2, LFA-1 or ICAM-1 mAb did not differentially affect Ag-induced proliferation among the clones. Moreover, antibody to CD28 did not influence Ag presentation by brain microvessel En or SM/P cells to Ag-specific Th1 and Th2 clones. These results suggest that: 1) different The subsets might require different signals for their activation; 2) different APC might provide different costimulatory signals for Th cell subsets; and 3) brain microvessel En and SM/P might play a differential role in induction of autoreactive T cell responses in the CNS.
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PMID:Differential activation of Th1 and Th2 CD4+ cells by murine brain microvessel endothelial cells and smooth muscle/pericytes. 810 Aug 44

The capacity of human peripheral blood (PB) dendritic cells (DC) and monocytes to facilitate T cell activation and the interaction molecules employed were compared. We have shown that precursors of DC constitute 2 to 3% of circulating PBMC, and can be isolated as CD33+CD14dim cells, whereas monocytes are CD33+CD14bright. Freshly obtained DC expressed similar densities of HLA-DR and the accessory molecules LFA-3, ICAM-1, and B7 as monocytes; after a 36-h incubation the expression of HLA-DR, ICAM-1, and B7 increased on both APC. Accessory cell function was examined in PB T cell cultures stimulated by suboptimal concentrations of immobilized mAb to CD3, and by stimulation of an allospecific T cell line. Freshly isolated monocytes and DC were comparable accessory cells in these assays, but their accessory function was increased by in vitro preincubation, although cultured DC and monocytes were comparably active. In contrast, DC were much more effective stimulators of freshly isolated allogeneic T cells than monocytes. DC were much more effective stimulators of freshly isolated allogeneic PB CD4+ naive and memory T cells than monocytes, whereas DC and monocytes were comparable accessory cells for memory and naive T cells stimulated with immobilized anti-CD3. The accessory molecules ICAM-1, LFA-3, and B7 were used comparably by DC and monocytes for accessory function in the presence of immobilized anti-CD3 and in the MLR, and none was unique for either APC population. These accessory molecules costimulated T cells in an additive fashion. Although immature blood DC and monocytes expressed minimal B7 and did not utilize it as an accessory molecule, B7 played an important role in the increased accessory function of differentiated APC. The results indicate that PB DC and monocytes function most efficiently after differentiation into mature cells that express increased amounts of MHC and other accessory molecules. Because DC and monocytes exhibit comparable accessory function in anti-CD3 T cell stimulation, differences in the expression of MHC molecules and/or their bound peptides are likely to explain the markedly enhanced capacity of DC to stimulate allogeneic PB T cells.
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PMID:Comparative accessory cell function of human peripheral blood dendritic cells and monocytes. 825 94

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