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)

Corneal grafts were until recently considered entirely devoid of resident APCs, giving rise to the tenet that alloantigen recognition is mediated exclusively by the indirect (host APC-dependent) pathway. The recent discovery of a resident myeloid corneal dendritic cell population that is normally MHC class II(-) but can readily up-regulate class II expression during inflammation led us to hypothesize that under certain conditions the direct pathway of allosensitization becomes operative. To test this, corneal allotransplants were performed in either inflamed (high-risk (HR)) or uninflamed (low-risk (LR)) host beds in mice, and the frequencies of host T cells activated via the direct pathway were determined. We found that directly primed CD4(+) T cells were detected in the HR but not LR setting, and these cells displayed a clear Th1 phenotype by 2 wk after grafting. Moreover, the use of MHC class II knockout donor tissue led to significantly enhanced survival of HR but not LR allografts. Finally, we show that donor corneal APC demonstrate high expression of CD40, CD80, and CD86 costimulatory molecules when derived from HR but not LR grafts. These data are the first to report that a functional donor APC-dependent direct response is elicited in corneal transplant hosts when the graft bed is inflamed and underscore the relevance of the graft microenvironment in dictating the pathway of allosensitization.
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PMID:Relevance of the direct pathway of sensitization in corneal transplantation is dictated by the graft bed microenvironment. 1538 77

Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligand (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
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PMID:Costimulation requirements of induced murine systemic autoimmune disease. 1549 42

T suppressor and regulatory cells have been shown to play an important role in the maintenance of central and peripheral tolerance thereby preventing allograft rejection, autoimmunity and allergy. We have previously described a distinct population of antigen-specific CD8(+)CD28(-) T suppressor cells (T(S)). These CD8(+)CD28(-) T(S) cells can be generated in vitro after multiple rounds of stimulation of human peripheral blood mononuclear cells (PBMCs) with either allogenic- or xenogeneic-donor APCs. CD8(+)CD28(-) T(S) cells are FOXP3+, MHC class I-restricted and tolerize both professional antigen presenting cells, such as dendritic cells (DC) and nonprofessional APC such as endothelial cells (EC) by up-regulating the cell surface expression of inhibitory receptors immunoglobulin-like transcript (ILT)-3 and ILT4 and down-regulating the expression of costimulatory molecules such as CD58 and CD86. Tolerized ILT3(high), ILT4(high) APC anergize CD4(+) T(H) cells and can induce the generation of antigen-specific CD4(+)CD25(+) T regulatory cells (T(R)) cells and CD8(+)CD28(-) T(S) cells. In this review, we present our recent studies on the molecular characterization of these antigen specific T suppressor cells and tolerogenic APC.
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PMID:Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. 1558 54

Human immunodeficiency virus-1 (HIV-1) Vpr encodes a 14 kDa protein that has been implicated in viral pathogenesis through in vitro modulation of several host cell functions. Vpr modulates cellular proliferation, cell differentiation, apoptosis and host cell transcription in a manner that involves the glucocorticoid pathway. To better understand the role of HIV-1 Vpr in host gene expression, approximately 9600 cellular RNA transcripts were assessed for their modulation in primary APC after treatment with a bioactive recombinant Vpr (rVpr) by DNA micro-array. As an extracellular delivered protein, Vpr down-modulated the expression of several immunologically important molecules including CD40, CD80, CD83 and CD86 costimulatory molecules on MDM (monocyte-derived macrophage) and MDDC (monocyte-derived dendritic cells). Maturation of dendritic cells (DC) is known to result in a decreased capacity to produce HIV due to a post-entry block of the HIV-1 replicative cycle. Based on the changes observed in the gene array, we analyzed maturation of DC generated from monocytes in tissue culture as influenced by Vpr. We observed that Vpr-treated immature MDM and MDDC were unable to acquire high levels of costimulatory molecules and failed to develop into mature DC, even in the presence of maturation signals. These studies have importance for understanding the interaction of HIV with the host immune system.
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PMID:HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro. 1561 22

The questions of whether mucosal tolerance and IgA immunity are mutually exclusive or can coexist and whether they represent priming of the local immune system through the same or different activation pathways are addressed. Two strategies were attempted: the first using cholera toxin (CT) or the enzymatically inactive receptor-binding B subunit of CT (CTB), and the second using CTA1-DD or an enzymatically inactive mutant thereof, CTA1R7K-DD. The CTA1-DD adjuvant is a fusion protein composed of the ADP-ribosylating part of CT, CTA1, and DD, which is derived from Staphylococcus areus protein A and targets the molecule to B cells. Here, we provide compelling evidence that delivery of antigen in the absence of ADP ribosylation can promote tolerance, whereas ADP-ribosyltransferase activity induces IgA immunity and prevents tolerance. By linking antigen to the ADP-ribosylating enzymes we could show that CT, although potentially binding to all nucleated cells, in fact, bound preferentially to dendritic cells (DCs) in vivo. On the other hand, DD-bound antigen was distinctly targeted to B cells and probably also to follicular dendritic cells (FDCs) in vivo. Interestingly, the CT and CTA1-DD adjuvants gave equally enhancing effects on mucosal and systemic responses, but appeared to target different APCs in vivo. CT- or CTB-conjugated antigen accumulated in mucosal and systemic DCs. Whereas only CT promoted an active IgA response, CTB induced tolerance to the conjugated antigen. Following intravenous injection of CT-conjugated antigen, DCs in the marginal zone (MZ) of the spleen were selectively targeted. Interestingly, CTB delivered antigen to the same MZ DCs, but failed to induce maturation and upregulation of costimulatory molecules in these cells. Thus, ADP-ribosylation was necessary for a strong enhancing effect of immune responses following CT/CTB-dependent delivery of antigen to the MZ DCs. Moreover, using CTA1-DD, antigen was targeted to the B cell follicle and FDC in the spleen after intravenous injection. Only active CTA1-DD, but not the inactive mutant CTA1R7K-DD, provided enhancing effects on immune responses. By contrast, antigen delivered by the CTA1R7K-DD stimulated specific tolerance in adoptively transferred T cell receptor transgenic CD4(+) T cells. Whether targeting of B cells suffices for tolerance induction or requires participation of DCs remains to be investigated. With CT we found that enzyme-dependent modulation of DCs affects migration, maturation, and differentiation of DCs, which resulted in CD4(+) T cell help for IgA B cell development. On the contrary, antigen presentation in the absence of ADP-ribosylating enzyme, as seen with CTB or CTA1R7K-DD, appears to expand specific T cells to a similar extent as enzymatically active CT or CTA1-DD, but fails to recruit help for germinal center (GC) formation and the necessary expansion of activated B cells. Also, the CD41 T cells that are primed in a suboptimal, tolerogenic, fashion do not migrate to the B cell follicle to provide T cell help. Thus, ADP-ribosylating enzymes may be used to selectively control the induction of an active IgA response or promote the development of tolerance. In particular, on the targeted APC, modulation of the expression of costimulatory molecules, CD80, CD86, CD83, and B7RP-1, plays an important role in the effect of the ADP-ribosylating CTA1-based adjuvants on the development of tolerance or active IgA immunity. For example, the expression of CD86 in vivo was a prominent feature of the enzymatically active CT or CTA1-DD adjuvants. By contrast, CD80 expression appeared not to be important in CTA1-augmented APCs for an adjuvant function.
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PMID:ADP-ribosylating bacterial enzymes for the targeted control of mucosal tolerance and immunity. 1568 58

The activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, the situation for naive CD8+ T cells is less clear. Although evidence indicates that induction of CD8+ T cell responses is also dependent on professional APC, the ability of some tumors, which do not express CD80/CD86, to induce CTL suggests that other pathways of costimulation exist for the activation of CD8+ T cells. We examined the ability of tumor cells expressing different levels of a tumor-specific Ag to directly prime CD8+ T cells. We demonstrate that CD8+ T cells are directly activated by tumor cells in a CD80/CD86-CD28 independent manner. In this system, costimulation requires ICAM-1/LFA-1 interaction. This results in the generation of CTL capable of inhibiting tumor growth in vivo, and maintaining long-term survival.
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PMID:The role of intercellular adhesion molecule-1/LFA-1 interactions in the generation of tumor-specific CD8+ T cell responses. 1574 73

It is well documented that a wide range of host-derived cell surface constituents is inserted within HIV type 1 (HIV-1) and located on the exterior of the virion. Although no virus-associated protein of host origin has been shown to be absolutely required for virus replication, studies have revealed that many of these proteins are functional and can affect several steps of the virus life cycle. In this study, we found that HIV-1 acquires peptide-loaded class II MHC (MHC-II) and the costimulatory CD86 molecules from the host cell. Moreover, we present evidence that virions bearing such peptide-loaded MHC-II and CD86 proteins can lead to activation of the transcription factors NF-kappa B and NF-AT in an Ag-specific human T cell line. A linear correlation was found between activation of NF-kappa B and the amount of peptide-loaded MHC-II molecules inserted within HIV-1. Finally, transcription of unintegrated and integrated HIV-1 DNA was promoted upon exposure of peptide-specific human T cells to viruses bearing both peptide-loaded MHC-II and CD86 proteins. These data suggest that HIV-1 can operate as an APC depending on the nature of virus-anchored host cell membrane components. It can be proposed that HIV-1 can manipulate one of its primary targets through the process of incorporation of host-derived proteins.
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PMID:HIV type 1 can act as an APC upon acquisition from the host cell of peptide-loaded HLA-DR and CD86 molecules. 1581 3

Identification and targeting of novel immunobiological factors that regulate the induction of Th1 cells are crucial for designing effective vaccines against certain intracellular pathogens, including Chlamydia. IL-10-deficient dendritic cells (DC) are potent APCs and effective cellular vaccines that activate a high frequency of specific Th1 cells. To elucidate the molecular basis for the potency of the IL-10-deficient APC system, we tested the hypothesis that Chlamydia Ag-primed IL-10 knockout (IL-10KO) DC are quantitatively and qualitatively distinct in their metabolic characteristics relating to T cell activation. Using a combination of RT-PCR, two-dimensional gel electrophoresis, and MALDI-TOF-based proteomics analyses, the transcriptional and translational activities of Chlamydia-pulsed DC from wild-type and IL-10KO mice were assessed. IL-10 deficiency caused early maturation and activation of pulsed DC (i.e., high CD11c, CD40, CD80, CD83, CD86, IL-1, IL-12, and the T cell-attracting chemokine CCL27/CTACK) and consequently an enhanced ability to process and present Ags for a rapid and robust T cell activation. Supporting comparative proteomics revealed further that IL-10 deficient DC possess specific immunobiological properties, e.g., the T cell-attracting chemokine CCL27/CTACK, calcium-dependent protein kinase, and the IL-1/IL-12 inducer, NKR-P1A (CD161), which differentiated them immunologically from wild-type DC that express molecules relating to anti-inflammatory, differentiative, and metabolic processes, e.g., the anti-IL-12 molecule peroxisome proliferator-activated receptor-alpha and thymidine kinase. Collectively, these results provide a molecular basis for the high Th1-activating capacity of IL-10KO APC and may provide unique immunomodulation targets when designing vaccines against pathogens controlled by T cell immunity.
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PMID:Molecular basis for the potency of IL-10-deficient dendritic cells as a highly efficient APC system for activating Th1 response. 1581 13

There is accumulating evidence that cell surface molecules may be transferred between cells during an encounter. The aim of these experiments was to determine whether transfer of allogeneic material to T cells could influence human alloresponses. CD4(+) cells were cocultured with M1 cell (human fibroblast) transfectants expressing HLA-DR1, CD80 and CD86 alone or in combination. Up to 95% of the allogeneic T cells became positive for HLA-DR and the appropriate costimulatory molecules after only 4 h of coculture. The phenomenon required cell contact and cell membrane fluidity because transfer was abolished by transwell separation of the M1 cells and the T cells or by pre-treatment of the APC with paraformaldehyde. Flow cytometric sorting of T cells after coculture and subsequent mixed lymphocyte assays demonstrated that the T cells that had acquired both HLA-DR and costimulatory molecules could act as potent antigen presenting cells. Finally, matured human dendritic cells were also shown to transfer these molecules to CD4(+) cells, which could then act as antigen presenting cells for unprimed T cells and for a cell line specific for an HLA-peptide complex acquired from the DCs. Taken together, these data suggest a novel pathway for the amplification of human alloresponses.
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PMID:Acquisition of HLA-DR and costimulatory molecules by T cells from allogeneic antigen presenting cells. 1594 19

Antigen presentation and T-cell activation are dynamic processes involving signaling molecules present in both APCs and T cells. Effective APC function and T-cell activation can be compromised by viral immune evasion strategies, including those of human immunodeficiency virus type 1 (HIV-1). In this study, we determined the effects of HIV-1 Vpr on one of the initial target of the virus, dendritic cells (DC), by investigating DC maturation, cytokine profiling, and CD8-specific T-cell stimulation function followed by a second signal. Vpr impaired the expression of CD80, CD83, and CD86 at the transcriptional level without altering normal cellular transcription. Cytokine profiling indicated that the presence of Vpr inhibited production of interleukin 12 (IL-12) and upregulated IL-10, whereas IL-6 and IL-1beta were unaltered. Furthermore, DC infected with HIV-1 vpr+ significantly reduced the activation of antigen-specific memory and recall cytotoxic-T-lymphocyte responses. Taken together, these results indicate that HIV-1 Vpr may in part be responsible for HIV-1 immune evasion by inhibiting the maturation of costimulatory molecules and cytokines essential for immune activation.
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PMID:Human immunodeficiency virus type 1 Vpr impairs dendritic cell maturation and T-cell activation: implications for viral immune escape. 1595 45


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