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At least 253 records · Page 14Linked to original sources
PubMed2004

CCL3/MIP-1alpha is a potent immunostimulator when coexpressed with interleukin-2 or granulocyte-macrophage colony-stimulating factor in a leukemia/lymphoma vaccine.

Chemokines orchestrate trafficking of immune effector cells during inflammation. Here we demonstrate that chemokines also serve to potentiate effector cell-mediated antineoplastic immune responses in vaccination strategies. As a critical mediator of inflammation, macrophage inflammatory protein 1alpha (CCL3/MIP-1alpha) attracts and stimulates both antigen-presenting and cytotoxic cells. In the A20 leukemia/lymphoma vaccine model, we explored the efficacy of MIP-1alpha in combination with interleukin-2 (IL-2) or granulocyte-macrophage colony-stimulating factor (GM-CSF). After subcutaneous injection of the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination vaccine, focal but pronounced infiltrates of CD4+ and CD8+ T cells were observed at the vaccination sites. In mice with preestablished leukemia/lymphoma, survival is significantly improved in animals treated with MIP-1alpha + GM-CSF- and MIP-1alpha + IL-2-secreting vaccines. Protection is superior in the MIP-1alpha + GM-CSF group, with the effects of MIP-1alpha and GM-CSF being synergistic. In contrast, suppression of lymphoblast proliferation by single-immunogen vaccines secreting MIP-1alpha, GM-CSF, or IL-2 alone does not translate to improved survival. The systemic protective effects afforded by the MIP-1alpha + IL-2 or MIP-1alpha + GM-CSF combination are mediated by different effector cell populations. In the MIP-1alpha + IL-2 group, antineoplastic defense is mediated by CD8+ T and NK cells, whereas in the MIP-1alpha + GM-CSF group CD4+ T cells are involved in addition to CD8+ cytotoxic T cells, underscoring that T cell help is critical for long-term protection. Thus combination of MIP-1alpha with different cytokines recruits different sets of effector cells into a potent antineoplastic immune response.

Animals↗
PubMed2004

Exogenous antigens are processed through the endoplasmic reticulum-associated degradation (ERAD) in cross-presentation by dendritic cells.

Antigen cross-presentation is critical in infectious and tumor immunity where cytotoxic T lymphocytes are induced by dendritic cells specifically equipped with cellular machineries to present exogenous antigens with major histocompatibility complex (MHC) class I molecules. To examine molecular mechanisms of antigen cross-presentation, we employed as a model system a murine dendritic cell line DC2.4 capable of presenting soluble antigens such as ovalbumin (OVA) with MHC class I. Here, we demonstrate that exogenously added OVA is accumulated in the endoplasmic reticulum (ER) and late endosomes followed by retrograde transport to the cytoplasm through the Sec61 transporter complexes, and that CHIP functions as an E3 ubiquitin-ligase for OVA degradation by proteasomes. This mechanism is essentially the same as that known as the ER-associated degradation (ERAD) in the quality control of secretary and membrane proteins.

Animals↗
PubMed2005

Highly efficient antigen targeting to M-DC8+ dendritic cells via FcgammaRIII/CD16-specific antibody conjugates.

Conjugates of peptide antigens with antibodies specifically recognizing surface molecules on dendritic cells (DC) represent an attractive approach to target antigens to antigen-presenting cells (APC) for the induction of specific T cell responses. The present study evaluates the potential of M-DC8(+) DC, a sub-population of professional APC in the blood, for an antibody-based vaccination strategy. We prepared, by chemical cross-linking, conjugates of peptide model antigens with antibodies directed against different cell surface molecules of DC. Antigen-peptide conjugates using an anti-CD16 (FcgammaRIII) antibody were most potent in inducing in vitro activation of a specific CD4(+) T cell response. They were at least 300 times more efficient than two other antibody-antigen conjugates and approximately 500 times more efficient than unconjugated antigen peptides. Our data demonstrate that specific antigen targeting via CD16 on M-DC8(+) DC is a promising vaccination approach for the efficient induction of specific CD4(+) T cell responses ex vivo, and perhaps in vivo.

Antibodies↗
PubMed2004

HIV-1 Nef equips dendritic cells to reduce survival and function of CD8+ T cells: a mechanism of immune evasion.

The accessory HIV-1 Nef protein is a crucial determinant for viral replication and pathogenesis. During HIV infection, loss of immune control in the setting of a strong and broad HIV-specific T-lymphocyte response, leads to a lethal outcome through AIDS. Moreover, dysfunction of dendritic cells (DCs) may contribute to the immune suppression associated with AIDS progression. We recently demonstrated that exogenous Nef selectively activates immature DCs manipulating their phenotypical, morphological, and functional developmental program. Here, we tracked whether Nef, targeting DCs, could be involved in the dysregulation of CD8+ T cell responses. We found that Nef inhibits the capacity of DCs to prime alloreactive CD8+ T cell responses down-regulating their proliferation and functional competence. This coincides with the induction of CD8+ T cell apoptosis. Nef oversees apoptotic killing of CD8+ T cells up-regulating TNF-alpha and FasL production by DCs and interfering with the death receptor pathway in CD8+ T cells and thus activating caspase 8. Our findings suggest that Nef may contribute to the immune evasion associated with HIV-1 infection, subverting DC biology. This may help explain the pleiotropic function that Nef plays during infection and makes this protein an attractive target for preventive and therapeutic intervention.

Apoptosis↗
PubMed2004

Cross-presentation, dendritic cell subsets, and the generation of immunity to cellular antigens.

Cross-presentation involves the uptake and processing of exogenous antigens within the major histocompatibility complex (MHC) class I pathway. This process is primarily performed by dendritic cells (DCs), which are not a single cell type but may be divided into several distinct subsets. Those expressing CD8alpha together with CD205, found primarily in the T-cell areas of the spleen and lymph nodes, are the major subset responsible for cross-presenting cellular antigens. This ability is likely to be important for the generation of cytotoxic T-cell immunity to a variety of antigens, particularly those associated with viral infection, tumorigenesis, and DNA vaccination. At present, it is unclear whether the CD8alpha-expressing DC subset captures antigen directly from target cells or obtains it indirectly from intermediary DCs that traffic from peripheral sites. In this review, we examine the molecular basis for cross-presentation, discuss the role of DC subsets, and examine the contribution of this process to immunity, with some emphasis on DNA vaccination.

Animals↗
PubMed2004

Targeting plasmid-encoded proteins to the antigen presentation pathways.

The antigen presentation pathways constitute a fulcrum on which adaptive immunity is balanced, and their manipulation should allow us to induce designer immune responses. The ease and rapidity with which DNA vaccines can be constructed and altered make them ideal candidates with which to test the various targeting strategies that have been conceived to date. These approaches and the mechanisms that may (or may not) underlie their success are reviewed in this article.

Animals↗
PubMed2004

B-Lymphocytes activated by CD40 ligand induce an antigen-specific anti-tumour immune response by direct and indirect activation of CD8(+) T-cells.

In this report, we describe the ability of CD40-ligand (CD40L)-activated, antigen-loaded B-cells to initiate antigen-specific anti-tumour immune responses in vivo. Mice immunized by means of intravenous administration of CD40L-activated B-cells loaded with an MHC class-I-binding peptide, and challenged with a tumour cell line expressing the same class-I epitope, showed a marked delay in tumour growth, compared to non-immunized controls or to mice receiving either freshly isolated B-cells or B-cells activated with lipopolysaccharide or interleukin-4. The ability of CD40L-activated B-cells to induce antigen-specific T-cell activation appeared to be through a combination of cross-presentation of antigen from activated B-cells to resident antigen-presenting cells and direct T-cell activation by the administered B-cells themselves. Immunization with CD40L-activated B-cells may, therefore, represent a means by which to stimulate anti-tumour CD8(+) T-cell responses in vivo.

Animals↗
PubMed2004

The genetic basis of immune and autoimmune responses.

HLA class I and class II molecules play a major role in the presentation of short, pathogen-derived peptides to T cells, a process that initiates the adaptive cellular and humoral immune responses. However, the factors governing a cell's ability to respond or not to particular peptides are still not completely understood. Taking the example of a viral infection, in tissues infected with a virus, viral particles are taken up by antigen-presenting cells and uncoated. The viral DNA or RNA enters the nucleus, where it replicates. mRNA enters the cytosol and is transcribed into proteins. These proteins are degraded in proteasomes and the resulting peptides (8-10 residues) are loaded onto class I molecules for export to the surface of the cells. In the meantime, the groove of the class II molecules is also preparing to accommodate peptides (12-24 residues) generated by the endocytic protein-processing pathway. The surface of the infected cell then becomes adorned with peptide-loaded human leukocyte antigen (HLA) molecules. CD4+ T helper lymphocytes engage class II molecules and elicit responses from B cells, which will ultimately lead to antibody production, whereas CD8+ T lymphocytes become cytotoxic T cells. As a consequence, the virus is eliminated from the body. However, certain mysteries and challenges remain. How can, as an exception to this rule, an autoimmune response be the escape from the perfect machinery? This review offers some hypotheses on how to see the problem through to its solution.

Autoimmune Diseases↗
PubMed2004

Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15R alpha by the same cells.

IL-15 is critical for generation of multiple lymphoid subsets. Recent data have demonstrated a unique aspect of responses to IL-15, in that cells bearing the IL-15Ralpha chain can bind soluble IL-15 and "transpresent" the cytokine to other cells, allowing the latter to respond to IL-15. However, it is unclear whether IL-15 is normally secreted and then becomes bound to surface IL-15Ralpha on bystander cells, or whether transpresentation is mediated by the same cells which synthesize IL-15. Using mixed bone marrow chimeric mice, we present evidence for the latter model, showing that development of NK cells and memory phenotype CD8 T cells necessitates that both IL-15 and IL-15Ralpha be expressed by the same population of cells. These data argue that soluble forms of IL-15 are irrelevant for physiological responses to this cytokine, and the implications of this finding are discussed.

Animals↗
PubMed2004

Activation of dendritic cells that cross-present tumor-derived antigen licenses CD8+ CTL to cause tumor eradication.

The fate of naive CD8(+) T cells is determined by the environment in which they encounter MHC class I presented peptide Ags. The manner in which tumor Ags are presented is a longstanding matter of debate. Ag presentation might be mediated by tumor cells in tumor draining lymph nodes or via cross-presentation by professional APC. Either pathway is insufficient to elicit protective antitumor immunity. We now demonstrate using a syngeneic mouse tumor model, expressing an Ag derived from the early region 1A of human adenovirus type 5, that the inadequate nature of the antitumor CTL response is not due to direct Ag presentation by the tumor cells, but results from presentation of tumor-derived Ag by nonactivated CD11c(+) APC. Although this event results in division of naive CTL in tumor draining lymph nodes, it does not establish a productive immune response. Treatment of tumor-bearing mice with dendritic cell-stimulating agonistic anti-CD40 mAb resulted in systemic efflux of CTL with robust effector function capable to eradicate established tumors. For efficacy of anti-CD40 treatment, CD40 ligation of host APC is required because adoptive transfer of CD40-proficient tumor-specific TCR transgenic CTL into CD40-deficient tumor-bearing mice did not lead to productive antitumor immunity after CD40 triggering in vivo. CpG and detoxified LPS (MPL) acted similarly as agonistic anti-CD40 mAb with respect to CD8(+) CTL efflux and tumor eradication. Together these results indicate that dendritic cells, depending on their activation state, orchestrate the outcome of CTL-mediated immunity against tumors, leading either to an ineffective immune response or potent antitumor immunity.

Adenovirus E1A Proteins↗
PubMed2005

Multiple intracellular routes in the cross-presentation of a soluble protein by murine dendritic cells.

Soluble heat shock fusion proteins (Hsfp) stimulate mice to produce CD8+ CTL, indicating that these proteins are cross-presented by dendritic cells (DC) to naive CD8 T cells. We report that cross-presentation of these proteins depends upon their binding to DC receptors, likely belonging to the scavenger receptor superfamily. Hsfp entered DC by receptor-mediated endocytosis that was either inhibitable by cytochalasin D or not inhibitable, depending upon aggregation state and time. Most endocytosed Hsfp was transported to lysosomes, but not the small cross-presented fraction that exited early from the endocytic pathway and required access to proteasomes and TAP. Naive CD8 T cell (2C and OT-I) responses to DC incubated with Hsfp at 1 microM were matched by incubating DC with cognate octapeptides at 1-10 pM, indicating that display of very few class I MHC-peptide complexes per DC can be sufficient for cross-presentation. With an Hsfp (heat shock protein-OVA) having peptide sequences for both CD4+ (OT-II) and CD8+ (OT-I) cells, the CD4 cells responded far more vigorously than the CD8 cells and many more class II MHC-peptide than class I MHC-peptide complexes were displayed.

ATP-Binding Cassette Transporters↗
PubMed2005

Herpes simplex virus infection of human dendritic cells induces apoptosis and allows cross-presentation via uninfected dendritic cells.

HSV efficiently infects dendritic cells (DCs) in their immature state and induces down-regulation of costimulatory and adhesion molecules. As in mice, HSV infection of human DCs also leads to their rapid and progressive apoptosis, and we show that both early and late viral proteins contribute to its induction. Because topical HSV infection is confined to the epidermis, Langerhans cells are expected to be the major APCs in draining lymph nodes. However, recent observations in murine models show T cell activation to be mediated by nonepidermal DC subsets, suggesting cross-presentation of viral Ag. In this study we provide an explanation for this phenomenon, demonstrating that HSV-infected apoptotic DCs are readily phagocytosed by uninfected bystander DCs, which, in turn, stimulate virus-specific CD8+ T cell clones.

Antigen Presentation↗
PubMed2005

The fate of low affinity tumor-specific CD8+ T cells in tumor-bearing mice.

A major challenge in tumor immunology is how best to activate the relatively low avidity self-specific and tumor-specific T cells that are available in the self-tolerant repertoire. To address this issue, we produced a TCR transgenic mouse expressing a class I-restricted hemagglutinin (HA)-specific TCR (clone 1 TCR) derived from a mouse that expressed HA as a self-Ag in the insulin-producing beta cells of the pancreatic islets (InsHA) mice. Upon transfer of clone 1 TCR CD8(+) T cells into InsHA mice, very few cells were activated by cross-presented HA, indicating that the cells were retained in InsHA mice because they ignored the presence of Ag, and not because they were functionally inactivated by anergy or tuning. Upon transfer into recipient mice in which HA is expressed at high concentrations as a tumor-associated Ag in spontaneously arising insulinomas (RIP-Tag2-HA mice), a high proportion of clone 1 cells were activated when they encountered cross-presented tumor Ag in the pancreatic lymph nodes. However, the activated cells exhibited very weak effector function and were soon tolerized. The few activated cells that did migrate to the tumor were unable to delay tumor progression. However, when HA-specific CD4 helper cells were cotransferred with clone 1 cells into RIP-Tag2-HA recipients and the mice were vaccinated with influenza, clone 1 cells were found to exert a significant level of effector function and could delay tumor growth. This tumor model should prove of great value in identifying protocols that can optimize the function of low avidity tumor-specific T cells.

Animals↗
PubMed2005

Mycobacterium tuberculosis heat shock fusion protein enhances class I MHC cross-processing and -presentation by B lymphocytes.

Exogenous heat shock protein (HSP):peptide complexes are processed for cross-presentation of HSP-chaperoned peptides on class I MHC (MHC-I) molecules. Fusion proteins containing HSP and Ag sequences facilitate MHC-I cross-presentation of linked antigenic epitopes. Processing of HSP-associated Ag has been attributed to dendritic cells and macrophages. We now provide the first evidence to show processing of HSP-associated Ag for MHC-I cross-presentation by B lymphocytes. Fusion of OVA sequence (rOVA, containing OVA(230-359) sequence) to Mycobacterium tuberculosis HSP70 greatly enhanced rOVA processing and MHC-I cross-presentation of OVA(257-264):K(b) complexes by B cells. Enhanced processing was dependent on linkage of rOVA sequence to HSP70. M. tuberculosis HSP70-OVA fusion protein enhanced cross-processing by a CD91-dependent process that was independent of TLR4 and MyD88. The enhancement occurred through a post-Golgi, proteasome-independent mechanism. These results indicate that HSPs enhance delivery and cross-processing of HSP-linked Ag by B cells, which could provide a novel contribution to the generation of CD8(+) T cell responses. HSP fusion proteins have potential advantages for use in vaccines to enhance priming of CD8(+) T cell responses.

Adjuvants, Immunologic↗
PubMed2005

Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection.

Alloreactive T lymphocytes are central mediators of graft-versus-host disease and allograft rejection. A public CTL clonotype with specificity for the alloantigens HLA-B*4402 and B*4405 is often expanded to large numbers in healthy HLA-B*0801(+) individuals, driven by cross-reactive stimulation with the common, persistent herpesvirus EBV. Since such alloreactive memory CTL expansions have the potential to influence transplantation outcome, altered peptide ligands (APLs) of the target HLA-B*0801-binding EBV peptide, FLRGRAYGL, were screened as specific antagonists for this immunodominant clonotype. One APL, FLRGRFYGL, exerted powerful antagonism of a prototypic T cell clone expressing this immunodominant TCR when costimulated with target cells presenting HLA-B*0801(FLRGRAYGL). Significantly, this APL also reduced the lysis of allogeneic target cells expressing HLA-B*4402 by up to 99%. The affinities of the agonist and antagonist complexes for the public TCR, measured using solution and solid-phase assays, were 8 and 138 muM, respectively. Surprisingly, the half-life of the agonist and antagonist complexes was similar, yet the association rate for the antagonist complex was significantly slower. These observations were further supported by structural studies that suggested a large conformational hurdle was required to ligate the immunodominant TCR to the HLA-B*0801 antagonist complex. By defining an antagonist APL against an immunodominant alloreactive TCR, these findings raise the prospect of exploiting such peptides to inhibit clinical alloreactivity, particularly against clonal T cell expansions that react with alloantigens.

Antigens, Viral↗
PubMed2003

Control of immune responses by savenger liver endothelial cells.

The liver appears to be an organ favoring the induction of immune tolerance rather than immunity. Among the hepatic cell populations possibly involved in regulation of immune responses, liver sinusoidal endothelial cells (LSEC) are well suited to fulfill this role. LSEC are resident cells lining the hepatic sinusoidal wall and therefore are in intimate contact with leukocytes passing through the liver. They are equipped with numerous scavenger receptors rendering antigen-uptake in these cells extremely efficient. Antigen processing and MHC-restricted presentation of exogenous antigens for CD4 as well as CD8 T cells occurs equally with high efficiency. Importantly, CD4 and CD8 T cells that engaged in cognate interaction with LSEC have a tolerant phenotype. Thus LSEC contribute an important immune function to the liver: control of the immune response against circulating soluble antigens.

Antigen Presentation↗
PubMed2004

[Construction of C3b(AN42) and OVA(257-264) fusion gene and functional analysis of the fusion protein].

AIM: To explore the role of complement system in the T cell activation. METHODS: OVA(257-264) CTL epitope and C3b(AN42) encoding genes were synthesized and cloned into expression vector pEGFP-N1. COS-7 cells were transfected with the recombinant plasmid pEGFP-N1. The expression of the fusion protein was determined by FACS. Twenty-four hours after transfection, cultural supernatants of the transfected cells were collected and added to Ana-1 cell culture. Laser confocal microscopy was used to detect the binding and presentation of the fusion protein by Ana-1 cells. RESULTS: C3b(AN42)-OVA(257-264) fusion protein was expressed in COS-7 cells. The fusion protein could bind to Ana-1 cells and OVA(257-264) CTL epitope was cross-presented on the surface of Ana-1 cells. CONCLUSION: The C3b(AN42)-OVA(257-264) fusion protein can express in COS-7 cells and possesses natural biological activity.

Animals↗