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)

APC use class II molecules of the MHC to present peptide Ag to Th cells. Interaction of the TCR and CD4 with the class II-peptide complex, together with co-stimulatory signals provided by the APC, activates the T cell. B lymphocytes express class II molecules and can also be induced to express co-stimulatory molecules, allowing them to act as APC to Th cells. In addition to T cell activation, class II binding by T cells has been shown to result in the transmission of signals to B cells. Signal transduction via MHC class II has been well documented in B cells of both mice and humans and is implicated in the processes of cellular adhesion, Ag presentation, and Ag-dependent B cell activation. The regions of the class II MHC molecule which are involved in signal transduction to the B cell are not clearly defined. However, previous studies have suggested that the beta chain of the alpha beta heterodimer has a predominant role in B cell signaling. To examine the role of the cytoplasmic domain of this molecule in class II-mediated signaling to a mouse B cell clone, we have prepared and analyzed a set of subclones expressing sequentially truncated forms of A beta b. Our results demonstrate that only the 8 membrane-proximal amino acids of the cytoplasmic domain are required for signaling. However, specific conserved amino acids within this minimal length are required for successful signal transduction; length alone is not sufficient. Examination of the signaling ability of these truncated beta chains suggests that conserved residues at positions 227 and 228 of the cytoplasmic domain may have particularly important effects on signal transduction. A beta b chains from which the entire cytoplasmic domain have been removed are still capable of transmitting a detectable, although reduced, signal to B cells. Thus, the transmembrane and/or extracellular domains may also be involved in the signaling process.
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PMID:Length and sequence requirements of the cytoplasmic domain of the A beta molecule for class II-mediated B cell signaling. 822 24

Ag administration into the portal vein can induce specific tolerance to that Ag, known as portal venous tolerance. Because intrahepatic mechanisms of tolerance induction are still largely undefined, we studied the in vitro response of OVA-sensitized Lewis rat lymphocytes to OVA presented by normal syngeneic rat Kupffer cells (KC) or KC that had been treated in vivo with gadolinium chloride (GD), a rare earth metal, which prevents the induction of portal venous tolerance. KC (2.5 x 10(4)) were able to present OVA to 5 x 10(5) OVA-sensitized APC-depleted lymphocytes as effectively as could lymph node APC. However, the use of GD-treated KC was associated with a significantly (P < 0.001) impaired response of OVA-sensitized APC-depleted lymphocytes to OVA. Although GD nearly abrogated in vivo phagocytosis of fluorescent latex beads by both KC and adherent splenocytes, expression of the class II MHC molecule (Ia) by KC was only slightly reduced by GD treatment. Unresponsiveness of OVA-sensitized lymphocytes to OVA was not related to enhanced PGE2 release by GD-treated KC, as determined both by PGE2 levels in culture supernatants and by cyclooxygenase inhibition. However, the marked ability of GD-treated KC to inhibit the response to OVA by primed lymph node populations containing lymphocytes and APCs supports an active suppressive mechanism. Prevention of the induction of portal venous tolerance by GD, the lack of in vitro KC Ag presentation by GD-treated KC, and active immunosuppression by GD-treated KC support a model of tolerance induction within the liver wherein Ag presentation and lymphocyte proliferation are necessary for the development of tolerance.
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PMID:Lymphocyte suppression by Kupffer cells prevents portal venous tolerance induction: a study of macrophage function after intravenous gadolinium. 838 86

T cell reactivity to alloantigens results from direct and indirect recognition of allogeneic MHC molecules and/or peptides. Although direct recognition is not self-MHC restricted, indirect recognition, the result of alloantigen processing and presentation by host APC, is restricted by the self (responder) MHC molecule to which the allopeptide has bound. We have studied the MHC restriction and TCR usage in T cell alloreactivity to a synthetic peptide corresponding to amino acid residues 21-42 of the DR beta 1*0101 molecule. T cell lines were developed by in vitro immunization of T cells from three responders carrying the DR beta 1*1101 allele with this peptide. In all three responders, reactivity to peptide 21-42 was restricted by the DR11 molecule. A limited usage of V beta genes was found in these T cell lines, all of which shared the expression of V beta 13.2. Because indirect recognition of allopeptide may play an important role in chronic, antibody-mediated allograft rejection, study of the TCR gene usage may contribute to the development of specific immunosuppression therapy.
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PMID:Limited usage of T cell receptor V beta genes by allopeptide-specific T cells. 846 63

Allogeneic tissues transplanted to mice treated with CD4- and CD8-specific Abs are often accepted indefinitely due to the induction of immunologic tolerance. When transplantation tolerance was induced to grafts mismatched at multiple minor histocompatibility loci, Ag specificity was inferred because third party grafts, mismatched at the MHC, were rejected normally. However, some "third party" grafts were either accepted, or rejected more slowly. Tolerant mice possess CD4+ cells, which suppress rejection by T cells reacting to the same grafts. Therefore, we hypothesized that tolerated third party grafts might share Ags with the original tolerizing graft, and that these Ags are a target for such suppression. To test this idea, we tolerized mice to a set of minor Ags (B10 minors) and challenged them with third party grafts that carried those minors, as well as an additional strong transplantation Ag, the class I MHC molecule, H-2Kb. This class I molecule acts as a good target for rejection in both naive mice and in mice tolerized to B10 minors. However, when this third party class I molecule is provided "linked" to those B10 minors on an F1 graft, rejection was significantly impaired. The data suggest that suppression within tolerant animals operates locally (perhaps on the same APC) via linked recognition. In addition, our preliminary findings suggest that suppression via linked recognition can also lead to tolerance to the third party Ag.
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PMID:T cell suppression in transplantation tolerance through linked recognition. 862 93

LEW rats with long-surviving (> 100 days) (DA x LEW)F1 kidney allografts were generated by treating the recipients with cyclosporine for 14 days after grafting. All rats were monitored after transplantation for the development of antibodies to intact donor class I MHC molecules. Cyclosporine completely suppressed the early antibody response to intact DA class I MHC molecules in all 19 LEW rats. However, 17 of the 19 rats developed antibodies between four and six weeks after grafting-i.e., between two and four weeks after the cessation of cyclosporine therapy, and maintained high levels of antibody to the donor class I molecules in spite of the long-term presence of the allograft. The 2 rats that did not produce antibodies to donor class I MHC molecules, along with one of the 17 that did produce antibodies, were immunized with a synthetic peptide corresponding to a region of the DA class I MHC molecule known to be recognized by LEW CD4+ T cells via the indirect recognition pathway. All 3 long survivors developed self APC-dependent CD4+ T cell proliferation to the immunizing donor peptides, and strong antibody responses to these peptides. However, none of these long survivors suffered rejection episodes as a consequence of the peptide immunization. In one of the two long-surviving rats without antibodies to intact donor class I MHC molecules at the time of peptide priming, the peptide priming resulted in the prompt development of strong antibodies to intact donor class I molecules. However, the other of these 2 rats did not produce such antibodies after peptide priming. Thus in this model of kidney allograft tolerance, with long-term exposure of the recipient's immune system to donor antigens without evidence of rejection, none of the animals develops tolerance for the indirect T cell recognition of donor class I MHC antigens. In occasional animals, B cells potentially reactive to intact donor class I molecules are present and are adequately exposed to antigen but are quiescent because of the absence of T cell help, perhaps as a consequence of reversible T cell suppression or anergy. In other occasional animals, B cell nonreactivity (anergy or tolerance) to intact donor class I molecules appears to develop.
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PMID:T and B cell responsiveness to donor class I MHC molecules and peptides in long survivors with kidney allografts. 863 70

Cytotoxic T lymphocyte activation and most probably tolerance induction, is dependent on antigen presentation by a specialized group of cells, APC, including macrophages, dendritic cells and B cells. Since T lymphocytes are, at least, the majority of the time MHC molecule class-specific, CD8+ T cells require antigen presented by MHC class I molecules. MHC class I molecules are, however, restricted to presenting endogenously produced antigenic peptides. Most threats to the organism are of exogenous origin and do not uniformly affect all or even most of the cells of an organism. This precludes the likelihood that any number of APC would be involved in every threatening situation, which raises the important question of how T lymphocytes are indeed activated, especially CD8+ T cells (MHC class I restricted).
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PMID:Cellular immunity: the final paradigm? 904 39

We describe the generation of three mAbs that recognize the complex of the class II MHC molecule IEk bound to a peptide derived from the carboxyl terminus of moth cytochrome c (residues 95-103). Reactivities of these mAbs are sensitive to single alterations in the sequence of both helices of the MHC molecule and to the bound peptide. The epitopes of these reagents are distinct but overlap substantially. One of these mAbs specifically blocks lymphokine release by T cells responsive to this complex but not others. We have used another to examine how the number of complexes on an APC is related to its ability to stimulate T cells. We find that 200-400 complexes per cell are necessary and sufficient to induce a degree of stimulation, whereas maximum stimulation is achieved only if more than 5000 complexes are present. The analysis indicates that T cell activation is a stochastic process.
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PMID:Determination of the relationship between T cell responsiveness and the number of MHC-peptide complexes using specific monoclonal antibodies. 1082 Feb 37

Susceptibility to collagen induced arthritis (CIA) in the murine model is linked to expression of the MHC class II alleles, I-Aq and I-Ar. We have examined the molecular basis for this MHC-linked susceptibility by studying the antigen presentation function of two class II molecules, I-Aq and I-Ap, that are closely related yet differ in mediating susceptibility to CIA. These class II molecules differ by only 4 amino acids, yet only mice expressing I-Aq develop CIA. Although the I-Ap molecule can bind the same immunodominant determinant from type II collagen as I-Aq, H-2p APC have difficulty generating I-Ap:CII peptide complexes when processing of CII is required. Immunization of H-2p mice with type II collagen (CII) generated only a weak T cell response when compared to H-2q mice, whereas immunization with the a CII peptide containing the dominant determinant induced a strong T cell response in both strains. In antigen presentation assays, H-2p APC were very inefficient in stimulating T cells when native CII was used as antigen, however they presented CII synthetic peptides with similar efficiency as H-2q APC. Processing and presentation of other antigens by H-2p APC was not affected. Using soluble class II binding assays, the affinity of I-Ap for the CII dominant peptide was 10 to 50 fold lower than I-Aq, however, this reduced affinity was not a general defect in I-Ap function. I-Aq and I-Ap had virtually identical affinities for binding other antigenic peptides. These data indicate that MHC-based susceptibility to autoimmunity may involve more than simple determinant selection and that the successful generation of an antigenic peptide by processing may be related to the overall affinity of the peptide for the MHC molecule.
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PMID:I-Aq and I-Ap bind and present similar antigenic peptides despite differing in their ability to mediate susceptibility to autoimmune arthritis. 1190 43

It is now generally accepted that CD4 T cells are critical players in the initiation of adaptive immune responses by contributing to the terminal differentiation of effector B cells or CD8+ T cells. It is therefore not surprising that CD4+ T cell activation is tightly controlled through the concerted action of a large number of molecular interactions. Activation requires not only the recognition of the appropriate antigen within a MHC molecule by the T cell receptor TCR but also the delivery of co-stimulatory signals by the antigen presenting cell APC . As a consequence therapeutic modulation of co-stimulatory molecules for instance with CTLA4Ig can lead to interference with T cell activation and consequently abrogation of pro-inflammatory manifestations mediated by cell types influenced by CD4+ T cells such as B cells CD8+ T cells or macrophages. This type of observations provided the rationale for the use of co-stimulatory blockade in autoimmunity and other immunopathology characterized by inappropriate immune activation such as rheumatoid arthritis RA . Several studies have also suggested that besides the non-specific anti-inflammatory effects co-stimulation blockade may in certain conditions promote the induction of long term immune tolerance.
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PMID:CTLA4Ig and the therapeutic potential of T cell co-stimulation blockade. 1884 7

T cell survival and homeostatic proliferation in the periphery requires T cell receptor (TCR) binding to restricting major histocompatability complex (MHC)-encoded molecules, as well as the availability of certain lymphokines. However, the exact mechanisms by which these signals interrelate and contribute to homeostasis are not understood. By performing T cell transfers into TCR transgenic hosts we detected a hierarchical order of homeostatic proliferation for T cells differing in MHC restriction, such that OT1 cells (K(b) restricted) proliferated in P14 (D(b)-restricted TCR) recipients, but not vice versa. Using K(b) mutant mice, we demonstrated that proliferation of OT1 cells in P14 recipients, as well as the ability of host OT1 cells to hinder the proliferation of donor P14 cells, were dependent on OT1-TCR binding to K(b) molecules. However, interclonal T cell competition was not mediated simply by competition for physical access to the MHC-bearing cell. This was shown in parabiotic pairs of OT1 and K(b) mutant mice in which P14 cells failed to proliferate, even though the OT1 cells could not interact with half of the APCs in the system. Thus, we conclude that the interaction between the TCR and restricting MHC molecule influences the ability to compete for trophic resources not bound to the stimulating APC. This mechanism allows a local competitiveness that extends beyond a T cell's specificity.
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PMID:T cell receptor contact to restricting MHC molecules is a prerequisite for peripheral interclonal T cell competition. 1901 5


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