Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II.
01 Aug 2004-Journal of Immunology (American Association of Immunologists)-Vol. 173, Iss: 3, pp 1987-1993
TL;DR: The present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.
Abstract: Strong CD4 + and CD8 + T cell responses are considered important immune components for controlling HIV infection, and their priming may be central to an effective HIV vaccine. We describe in this study an approach by which multiple CD4 + and CD8 + T cell epitopes are processed and presented from an exogenously added HIV-1 Gag-p24 peptide of 32 aa complexed to heat shock protein (HSP) gp96. CD8 + T cell recognition of the HSP/peptide complex, but not the peptide alone, was inhibited by brefeldin A, suggesting an endoplasmic reticulum-dependent pathway. This is the first report to describe efficient processing and simultaneous presentation of overlapping class I- and class II-restricted epitopes from the same extracellularly added precursor peptide complexed to HSP. Given previous reports of the strong immunogenicity of HSP/peptide complexes, the present data suggest that HSP-complexed peptides containing multiple MHC class I- and class II-restricted epitopes represent potential vaccine candidates for HIV and other viral infections suitable to induce effective CTL memory by simultaneously providing CD4 T cell help.
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TL;DR: Endogenous HSPs are key players in the modulation of these two modes of inflammation, and as such, they are potential targets for new and more efficient therapies for cancer, infections, and autoimmunity.
Abstract: Heat shock proteins (HSPs) have been reported to stimulate the immune system via innate receptors. However, the role of HSPs as endogenous adjuvants has been challenged by reports claiming that pure HSPs are not innate ligands; it is only the bacterial molecules trapped by the HSPs that can signal the innate immune system. In this review, we discuss data suggesting that both views, in essence, are correct; pure HSPs are indeed innate immunostimulators, but HSPs can also function as transducers of pathogen signals. In other words, HSPs perform diverse functions in two alternative modes of inflammation: sterile inflammation, which results from endogenous stimuli and is necessary for body maintenance, and septic inflammation, which protects us from environmental pathogens. Endogenous HSPs are key players in the modulation of these two modes of inflammation, and as such, they are potential targets for new and more efficient therapies for cancer, infections, and autoimmunity.
222 citations
TL;DR: In addition to maintaining cell homeostasis under physiological and stress conditions, some heat shock proteins (HSPs) are potent inducers of immunity and have been harnessed as vaccine adjuvants targeted to cancers and infections.
130 citations
TL;DR: The history and current status of HSP-based immunotherapies and vaccination strategies in the treatment of cancer are recapitulate.
Abstract: Intracellular residing heat shock proteins (HSPs) with a molecular weight of approximately 70 and 90 kDa function as molecular chaperones that assist folding/unfolding and transport of proteins across membranes and prevent protein aggregation after environmental stress. In contrast to normal cells, tumor cells have higher cytosolic HSP70 and Hsp90 levels which contribute to tumor cell propagation, metastasis and protection against apoptosis. In addition to their intracellular chaperoning functions, extracellular localized and membrane-bound HSPs have been found to play key roles in eliciting anti-tumor immune responses either by acting as carriers for tumor-derived, immunogenic peptides, as adjuvants for antigen presentation or as targets for the innate immune system. The interaction of HSP-peptide complexes or peptide-free HSPs with receptors on antigen presenting cells (APCs) promotes the maturation of dendritic cells (DCs), results in an up-regulation of MHC class I and class II molecules, induces secretion of pro- and anti-inflammatory cytokines, chemokines, and immune modulatory nitric oxides and thus integrate adaptive and innate immune phenomena. Herein, we aim to recapitulate the history and current status of HSP-based immunotherapies and vaccination strategies in the treatment of cancer.
128 citations
Cites background from "Heat shock protein-mediated cross-p..."
...Immunogenic peptides chaperoned by gp96 and HSP70s were not only found to elicit specific immune responses against cancer (24, 25) but also against infectious diseases (26, 27), indicating the broad applicability of HSP-based vaccines....
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Patent•
22 Jul 2009
TL;DR: A method for the repair of a unit, by specific diagnosis of the undesired state, and its appropriate repair, using said specific diagnosis as a means to repair in an appropriate way said unit.
Abstract: A method for the repair of a unit, by specific diagnosis of the undesired state, and its appropriate repair, using said specific diagnosis as a means to repair in an appropriate way said unit. The diagnosis and repair processes may involve chemical, physical, or mechanical means. The units being diagnosed and repaired include live matter (e.g. human beings, animals, plants) as well as non-live matter (e.g. buildings, electronic equipment, polymer materials).
106 citations
TL;DR: The basis of the tumorspecific immunogenicity of these molecules lies not in the molecules themselves but in the array of peptides, including antigenic peptides chaperoned by them.
Abstract: Heat shock proteins (HSPs) are primordial and abundant molecules expressed in all cells. Publications starting in 1984 have shown that immunization of mice, rats, and frogs with purified preparations of selected HSPs isolated from cancers leads to protective immunity against the cancer used as the source of the HSP. The basis of the tumorspecific immunogenicity of these molecules lies not in the molecules themselves but in the array of peptides, including antigenic peptides chaperoned by them. These experiments and the ideas derived from them form the basis of an approach to immunotherapy for human cancer that began in 1995 and is now in full swing.
101 citations
References
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TL;DR: Results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory and show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses to reinfection.
Abstract: Although primary CD8 responses to acute infections are independent of CD4 help, it is unknown whether a similar situation applies to secondary responses. We show that depletion of CD4 cells during the recall response has minimal effect, whereas depletion during the priming phase leads to reduced responses by memory CD8 cells to reinfection. Memory CD8 cells generated in CD4+/+ mice responded normally when transferred into CD4−/− hosts, whereas memory CD8 cells generated in CD4−/− mice mounted defective recall responses in CD4+/+ adoptive hosts. These results demonstrate a previously undescribed role for CD4 help in the development of functional CD8 memory.
1,482 citations
"Heat shock protein-mediated cross-p..." refers background in this paper
...the induction of functionally competent memory CTL (3, 4)....
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...This need for CD4 T cell help in the induction phase of CTL responses is highlighted most clearly by recent reports in murine systems describing the induction of functionally impaired memory CTL when CD4 T cell responses were not induced simultaneously (3, 4)....
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...Taken together, these data demonstrate that multiple HLA class I-restricted (5) and class II-restricted (3) epitopes can be processed and presented from the 32-mer precursor peptide coupled to HSP and that for re-presentation of Ag, HSP receptors may be required....
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TL;DR: It is reported here that heat shock proteins (HSP), the most abundant and conserved mammalian molecules, constitute such an internal signal that provides a unified mechanism for response to internal and external stimuli.
Abstract: Dendritic cells (DC) are key components of innate and adaptive immune responses. The identity of endogenous signals that activate DC is a crucial and unresolved question. We report here that heat shock proteins (HSP), the most abundant and conserved mammalian molecules, constitute such an internal signal. Necrotic but not apoptotic cell death leads to release of HSP gp96, calreticulin, hsp90 and hsp70. HSP stimulate macrophages to secrete cytokines, and induce expression of antigen-presenting and co-stimulatory molecules on the DC. The HSP gp96 and hsp70 act differentially, and each induces some but not all molecules. HSP interact with these antigen-presenting cells through the highly conserved NF-kappa B pathway. As HSP are intracellular, abundant and soluble, their presence in the extra-cellular milieu and the consequent activation of antigen-presenting cells (APC) constitutes an excellent mechanism for response to cell death. As HSP are conserved from bacteria to mammals, the ability of HSP to activate APC provides a unified mechanism for response to internal and external stimuli.
1,341 citations
TL;DR: A previously undescribed role for CD4 help in promoting protective CD8 memory development is highlighted in mice that lack CD4+ T cells that mount a primary CD8 response to Listeria monocytogenes.
Abstract: The CD8+ cytotoxic T cell response to pathogens is thought to be CD4+ helper T cell independent because infectious agents provide their own inflammatory signals. Mice that lack CD4+ T cells mount a primary CD8 response to Listeria monocytogenes equal to that of wild-type mice and rapidly clear the infection. However, protective memory to a challenge is gradually lost in the former animals. Memory CD8+ T cells from normal mice can respond rapidly, but memory CD8+ T cells that are generated without CD4 help are defective in their ability to respond to secondary encounters with antigen. The results highlight a previously undescribed role for CD4 help in promoting protective CD8 memory development.
1,279 citations
TL;DR: It is shown here that complexes of peptides with heat shock proteins hsp90, calreticulin, and hsp70 are also taken up by macrophages and dendritic cells and re-presented by MHC class I molecules.
1,119 citations
"Heat shock protein-mediated cross-p..." refers background in this paper
...Therefore, to facilitate the analyses and, moreover, to be less constrained by obtaining sufficient DC from individuals with the appropriate HLA types, a number of well-established cell lines and in vitro generated B-LCL were assessed for the expression of CD91, a common receptor for HSP (10)....
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...Upon cell stress and cell death, such HSP/Ag complexes are released and taken up by professional APCs through HSP receptors such as CD91, enabling them to cross-present Ag-derived CTL and Th cell epitopes (7, 10, 11)....
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TL;DR: A subset of the proteasome beta-subunits and one of the accessory complexes are upregulated by gamma-interferon and affect the generation of peptides to promote more efficient antigen recognition and bind lipid-based ligands within the endocytic pathway.
Abstract: ▪ Abstract Classical class I molecules assemble in the endoplasmic reticulum (ER) with peptides mostly generated from cytosolic proteins by the proteasome. The activity of the proteasome can be modulated by a variety of accessory protein complexes. A subset of the proteasome β-subunits (LMP2, LMP7, and MECL-1) and one of the accessory complexes, PA28, are upregulated by γ-interferon and affect the generation of peptides to promote more efficient antigen recognition. The peptides are translocated into the ER by the transporter associated with antigen processing (TAP). A transient complex containing a class I heavy chain–β2 microglobulin (β2m) dimer is assembled onto the TAP molecule by successive interactions with the ER chaperones calnexin and calreticulin and a specialized molecule, tapasin. Peptide binding releases the class I–β2m dimer for transport to the cell surface, while lack of binding results in proteasome-mediated degradation. The products of certain nonclassical MHC-linked class I genes bind p...
1,067 citations
"Heat shock protein-mediated cross-p..." refers methods in this paper
...After digestion by the proteasome, the processed peptides are translocated to the endoplasmatic reticulum by the TAP heterodimer (41)....
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