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

Dendritic cells (DC) are potent APC that, in mature form, can be distinguished from other mononuclear cells on the basis of their distinct morphology, absence of lineage markers, and dense expression of MHC and costimulatory molecules. While comparing different DC preparation methods, we observed that DC derived from cultured PBMC that had been depleted of CD2+ cells before culture were functionally distinct from DC derived from PBMC that had not been depleted of CD2+ cells. Thus, both types of DC stimulated allogeneic T cells to proliferate in the MLR, but only DC derived from CD2+ precursors could sensitize naive T cells to soluble Ags such as keyhole limpet hemocyanin and HIV gp160 glycoprotein. Subsequent studies confirmed the existence of CD2+ and CD2- DC precursor populations among HLA-DRbright, lineage-negative PBMC. Immediately after their isolation, these populations were morphologically similar to one another by light and electron microscopy, and neither had substantial Ag-presenting activity. After culture for 24 to 48 h with supernatant from PHA-activated PBMC, both populations developed dendrites, formed clusters with T cells, and stimulated allogeneic T cell responses in the MLR as well as autologous T cell responses to tetanus toxoid, a recall Ag. However, CD2+ DC precursors alone gave rise to APC that presented soluble Ags to naive CD4+ T cells, a property that could be inhibited by Abs to CD4, CD11a, and CD28 on T cells or CD86 on DC. The expression of CD54 and CD86 on CD2+ DC precursors was increased markedly after their culture and differentiation, while the expression of these molecules on CD2- DC precursors was not remarkably changed. These findings reveal the existence of two functionally distinct populations of DC, each derived from a phenotypically distinct precursor present in monocyte-depleted peripheral blood.
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PMID:Dendritic cells that process and present nominal antigens to naive T lymphocytes are derived from CD2+ precursors. 903 58

A previously developed experimental system was applied to obtain qualitative and quantitative data on the contribution of TCR-, CD4- and CD28-mediated signalling in the activation of an antigen specific T-cell hybridoma. All the three signal transducing receptors were stimulated by their natural ligands, and intermediate and late responses of an I-Ed restricted, CD4 +, influenza HA specific murine T-hybridoma (IP-12-7) were monitored by measuring the concentration of intracellular calcium [Ca2+]i and secreted IL-2. This type of analysis of T-cell activation revealed: (i) calcium mobilization induced by peptide loaded APC requires rapid conjugate formation; (ii) a direct correlation between the magnitude of the intermediate and the late responses was observed as a consequence of differential TCR ligation modulated by peptide dose or by the presence CD4; (iii) considering the APC/peptide and T/APC ratios, the concentration dependence of the intermediate and late responses was similar in both assays but a substantial difference in the sensitivity of the two methods was observed; (iv) CD4 mediated signalling has a co-stimulatory effect predominantly at suboptimal in vitro conditions; and (v) sustained increase of [Ca2+]i as well as the production of high concentrations of IL-2 is highly dependent on the CD28-B7 interaction. These results demonstrate that distinct peptide doses and the presence or absence of CD4 result in quantitative changes in T-cell responses, while the degree of CD28 mediated signalling has a qualitative affect on the outcome of T-cell activation, revealed by complete or partial inhibition of IL-2 secretion as a result of limited CD28-B7 interaction as well as by alteration in the duration and time kinetics of the calcium response.
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PMID:Collaboration of TCR-, CD4- and CD28-mediated signalling in antigen-specific MHC class II-restricted T-cells. 905 68

Recent studies in several laboratories have advanced the concept that during cellular rejection, the allograft undergoes a stress response which regulates the expression of stress proteins (or heat shock proteins, hsp) and triggers the recruitment and activation of hsp-reactive lymphocytes. In a rat model of heterotopic heart transplants we have found that allograft-infiltrating lymphocytes respond to recombinant mycobacterial hsp and irradiated syngeneic spleen cells as a source of self-APC (antigen-presenting cells). This report describes T cell clones generated by culturing ACI into Lewis rat cardiac allograft-derived lymphocytes with mycobacterial hsp71, syngeneic spleen cells and IL-2 (interleukin-2). Two groups of self-APC-reactive T cell clones have been distinguished, all of them are CD3+, CD4+, CD8-. One group is referred to as hsp71-dependent, autoreactive T cells because these clones respond to self-APC but only in the presence of hsp71. No reactivity is seen with mycobacterial hsp65 or when hsp71 is tested with allo-PC from ACI donors or third-party APC from Brown Norway (BN) rats. Treatment of hsp71 with trypsin, polymyxin B or ATP-agarose chromatography abrogates the hsp71 effect thus indicating that structurally intact hsp71 must interact with self-APC which then activate hsp71-dependent, autoreactive T cells. The second group of clones reacts to self-APC and while their response does not require the presence of hsp71, their proliferation is often augmented by hsp71 but not by hsp65. These hsp71-independent, autoreactive clones do not respond to allo-APC from ACI donors or third-party APC from BN rats. Polymyxin or trypsin treatment had no significant effect on their proliferative responses. The data with the anti-TCR-alpha beta monoclonal antibody R73 offer additional evidence for two functionally different types of self-APC reactive CD4 cells infiltrating the allograft. R73 inhibits the proliferation of self-APC induced responses of hsp-71-independent clones as well as the allo-APC induced responses of alloreactive T cell clones. In contrast, this antibody augments the responses of hsp71-dependent T cells. Moreover, these clones can also proliferate in response to self-APC when hsp71 is substituted by R73. The hsp71-dependency of self-APC reactive T cell reactivity represents a previously unrecognized mechanism of cellular immunity to allografts. This mechanism might be related to the peptide binding properties of hsp71 and the ability of stress proteins to function as molecular chaperones in antigen processing.
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PMID:Identification of two types of autoreactive T lymphocyte clones cultured from cardiac allograft-infiltrating cells incubated with recombinant mycobacterial heat shock protein 71. 910 36

Peptides that consist of two tandemly repeated epitopes joined by a flexible linker have an increased affinity for class II molecules and are more potent at inducing proliferation of T cell clones than monomeric epitopes. The increase in potency of peptides with two epitopes for individual T cell clones is proportional to the relative CD4 dependence of the clones. We show that epitope dimers activate T cell clones that respond sub-optimally to monomeric epitopes presented by APC from HIV-infected donors. We hypothesize that HIV+ APC normally fail to stimulate the clones because virally encoded gp 120 sequesters CD4 from the activation complex, but epitope dimers overcome this effect because they are better able to recruit CD4. The alpha beta heterodimer of human class II (HLA-DR1) is further ordered as a dimer of heterodimers (superdimer) at least in its crystal form. Since class II molecules have an open-ended antigen binding groove, the superdimer is theoretically permissive of stable binding of two peptide epitopes linked in tandem. Our data support a role for the MHC class II dimer of heterodimers in amplifying the proliferative response of T cells to antigen by dint of the superdimers having a higher affinity for CD4 than the nominal class II alpha beta heterodimers.
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PMID:Tandem peptide epitopes facilitate CD4-dependent activation of T cell clones. 910 67

CD4+ and CD8+ T cells emerge from thymic selection expressing a TCR restricted by MHC class II (TCRII) and MHC class I (TCRI), and upon Ag stimulation develop respectively into Th and CTL effector cells. The influence of thymic differentiation and antigenic stimulation on the determination of T cell functions was studied, with CD4+ T cells expressing a transgenic TCRI that reacts with the class I alloantigen H-2K(b) in a CD8-independent fashion. Such T cells additionally express a TCR, probably TCRII, in which the transgenic TCR beta-chain is associated with endogenously rearranged TCR alpha-chains. Upon in vitro stimulation with H-2K(b)-expressing cells, both CD8+ and CD4+ transgenic TCR+ T cells developed into CTL capable of killing Ag-expressing target cells through a perforin-dependent mechanism, and secreted IL-2 and IFN-gamma. Fas ligand-dependent killing could also be induced in both CD8+ and CD4+ in vitro stimulated T cells. The capacity to secrete IL-4 was restricted to the CD4+ T cells, however, suggesting that both CD8/CD4-shared and CD4-unique programs can be elicited by stimulation of CD4 T cells through a TCRI. Acquisition of CTL function was also induced upon class II alloantigen stimulation through the endogenously rearranged TCRII, which represents a polyclonal set of TCRs. IL-2, IFN-gamma, and after restimulation, IL-4, were also produced. Thus: 1) events associated with intrathymic selection influence the gene program activated in response to the same TCRI/APC interaction; and 2) CD4+ T cells expressing a TCRI and a TCRII can activate the same gene program after engagement of either one of these TCRs.
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PMID:Class I- and class II-reactive TCRs coexpressed on CD4+ T cells both trigger CD4/CD8-shared and CD4-unique functions. 914 64

Lipopolysaccharide (LPS) from gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other APC. We show here that, under in vivo conditions, LPS also induces strong stimulation of T cells. As manifested by CD69 upregulation, LPS injection stimulates both CD4 and CD8(+) T cells, and, at high doses, stimulates naive (CD44(lo)) cells as well as memory (CD44(hi)) cells. However, in terms of cell division, the response of T cells after LPS injection is limited to the CD44(hi) subset of CD8(+) cells. In contrast with B cells, proliferative responses of CD44(hi) CD8(+) cells require only very low doses of LPS (10 ng). Based on studies with LPS-nonresponder and gene-knockout mice, LPS-induced proliferation of CD44(hi) CD8(+) cells appears to operate via an indirect pathway involving LPS stimulation of APC and release of type I (alpha, beta) interferon (IFN-I). Similar selective stimulation of CD44(hi) CD8(+) cells occurs in viral infections and after injection of IFN-I, implying a common mechanism. Hence, intermittent exposure to pathogens (gram-negative bacteria and viruses) could contribute to the high background proliferation of memory-phenotype CD8(+) cells found in normal animals.
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PMID:T cell stimulation in vivo by lipopolysaccharide (LPS). 918 80

By selective depletion of CD4 and CD8 T cells in vivo using the respective mAbs, we demonstrate that CD4 T cells are necessary for skin graft rejection against thymus leukemia (TL) Ag. The skin expressing T3b-TL Ag from transgenic C3H Tg.Con.3-1 mice given chimeric H-2Kb/T3b-TL gene was rejected when grafted onto C3H/He recipient mice. Depletion of CD4, but not of CD8, T cells blocked rejection. CD8 CTL were generated in MEM (control)-treated C3H/He recipient mice, while Thy-1+ CD4- CD8- CTL were generated in CD8-depleted recipient mice after rejection. However, no CTL were generated in CD4-depleted or both CD4- and CD8-depleted recipient mice. Thus, the generation of both CD8 and Thy-1+ CD4- CD8- CTL was dependent on CD4 T cells. Ab blocking indicated that both CD8 and Thy-1+ CD4- CD8- CTL were TCR alphabeta and recognized TL Ag. We furthermore demonstrated that CD4 T cells in spleen cells from C3H/He mice that had rejected C3H Tg.Con.3-1 skin showed a weak, but significant, proliferative response to in vitro stimulation with mitomycin C-treated C3H Tg.Con.3-1 spleen cells. Analysis of the reactivity of bulk CD4 T cell lines to 73 synthetic overlapping peptides encompassing the entire T3b-TL molecule showed that CD4 T cells recognized multiple epitopes on the T3b-TL molecule in an APC-dependent manner.
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PMID:Requirement of CD4 T cells for skin graft rejection against thymus leukemia (TL) antigen and multiple epitopes on the TL molecule recognized by CD4 T cells. 920 Apr 51

Recent data suggest that CD40 ligand (CD40L)-CD40 interactions are essential for up-regulation of costimulatory activity on APC and that efficient induction of CD40L may be pivotal to the success of a CD4 T cell response. CD40L is regulated primarily by TCR signaling, but high level expression on a naive T cell appears to require additional interactions between T cell coreceptors and APC accessory molecules. The data reported here show that resting B cells presenting peptide Ag, in contrast to both dendritic cells and preactivated B cells, induce very little CD40L on naive CD4 cells, which in turn is insufficient to promote APC costimulatory activity. We also show, however, that previously activated effector T cells have enhanced responsiveness to Ag when accessory molecule help is limiting and consequently can express high levels of CD40L after interaction with resting B cells. High level CD40L expression correlated with B cell activation and up-regulation of costimulatory activity; however, blocking studies showed that CD40L was only partially responsible for these phenomena. These studies reinforce the notion that resting B cells may be tolerogenic for naive CD4 cells in part because of inefficient CD40L induction. The data also suggest that a successful primary T cell response will only occur if either the initial interaction is with a dendritic cell followed by subsequent interactions of the effector T cells with resting APC or if nonspecific inflammatory stimuli up-regulate accessory molecule expression on resting APC before an encounter with the naive T cell.
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PMID:CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response. 927 17

CD4 T cell activation requires stable contact with APCs. In the present study we demonstrate that anti-CD3-stimulated memory but not naive CD4 T cells fail to form stable conjugates with MHC class II+ APCs and fail to become activated. Early deconjugation by memory CD4 T cells is dependent on CD4-MHC class II interactions in that conjugation is restored when the APC do not express MHC class II or when the class II molecule is mutated at the CD4 binding site. Furthermore, MHC class II-restricted memory-T cells from CD4-deficient mice form stable conjugates, indicating that the CD4 molecule expressed on naive and memory CD4 T cells differs in function and regulates memory but not naive CD4 T cell adhesion to syngeneic APCs in the absence of Ag. This mechanism may have implications for Ag-primed memory CD4 T cells in that primed memory cells, which express an increased number of adhesion molecules, may dissociate from cells in the absence of CD4/TCR co-ligation by the same MHC class II molecule. This would prevent bystander activation and assure efficient recirculation of activated memory T cells in search of Ag-bearing target cells.
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PMID:Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction. 930 Jun 74

Tolerance is thought to occur when Ag is presented to T cells in the absence of costimulatory interactions from APC accessory molecules. Of the professional APC, the resting B cell may be the main tolerizing cell in vivo. We have analyzed several aspects of activation of naive transgenic CD4 cells stimulated with resting or activated B cells presenting peptide Ag. Similar results were obtained with stimulation from peptide presenting fibroblast APC lacking or expressing B7-1 with intracellular adhesion molecule-1. TCR ligation with little or no accessory molecule coreceptor engagement induced efficient blastogenesis; up-regulation of CD25, CD44, CD69, CD95 and CD71; and down-regulation of CD62L over a 48-h period. Accessory molecule help enhanced the expression of CD25, CD44, CD69, and CD71, but to very modest degrees. Only two molecules, CD40 ligand and IL-2, were found to be extremely dependent on accessory molecule help, with little or no expression evident with peptide presented on resting B cells or class II-positive fibroblasts. T cells induced on resting B cells expanded minimally over 3 days, and this was followed by extensive cell death and hyporesponsiveness of the resulting cells. These studies suggest that under tolerizing conditions, such as Ag presentation by resting B cells, much of the naive CD4 response is induced efficiently. Partial activation, however, may be the overall result due to the lack of CD40 ligand expression, which may regulate costimulatory activity in APC and, in turn, may contribute to limiting the production of IL-2 required for T cell expansion and survival.
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PMID:Partial activation of naive CD4 T cells and tolerance induction in response to peptide presented by resting B cells. 931 24


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