Interaction of TLR2 and TLR4 Ligands with the N-terminal Domain of Gp96 Amplifies Innate and Adaptive Immune Responses

Warger, Tobias; Hilf, Norbert; Rechtsteiner, Gerd; Haselmayer, Philipp; Carrick, Deanna M.; Jonuleit, Helmut; Landenberg, Philipp von; Rammensee, Hans‐Georg; Nicchitta, Christopher V.; Radsak, Markus P.; Schild, Hansjoerg

doi:10.1074/jbc.m502900200

Cited by 120 publications

(95 citation statements)

References 53 publications

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“…The intervention strategy in the combination of OK-432 and up-regulated HSPs may act synergistically through the fusion process and result in efficient Ag processing and presentation in the context of up-regulated MHC and costimulatory molecules. Our findings are consistent with those of a recent study that has found that pathogen-associated molecules cooperate efficiently with damage-associated molecules, such as HSPs, in activating DCs (58).…”

Section: Discussionsupporting

confidence: 83%

“…Ag presentation by DCs, in the absence of proper costimulation, induces tolerance (1). In particular, recent studies suggest that TLR-agonist CpG ODNs or conserved pathogen-associated molecular patterns, such as OK-432, start the DC maturation process, which is a critical event in the induction of full effector function in T cells (20,31,32,35,41,57,58). Therefore, we next investigated whether DCs activated by a combination of TLR ligation and up-regulated HSPs enhance the immunogenicity of FCs.…”

Section: Discussionmentioning

confidence: 99%

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Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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Dendritic cell (DC)/tumor cell fusion cells (FCs) can induce potent CTL responses. The therapeutic efficacy of a vaccine requires the improved immunogenicity of both DCs and tumor cells. The DCs stimulated with the TLR agonist penicillin-killed Streptococcus pyogenes (OK-432; OK-DCs) showed higher expression levels of MHC class I and II, CD80, CD86, CD83, IL-12, and heat shock proteins (HSPs) than did immature DCs. Moreover, heat-treated autologous tumor cells displayed a characteristic phenotype with increased expression of HSPs, carcinoembryonic Ag (CEA), MUC1, and MHC class I (HLA-A2 and/or A24). In this study, we have created four types of FC preparation by alternating fusion cell partners: 1) immature DCs fused with unheated tumor cells; 2) immature DCs fused with heat-treated tumor cells; 3) OK-DCs fused with unheated tumor cells; and 4) OK-DCs fused with heat-treated tumor cells. Although OK-DCs fused with unheated tumor cells efficiently enhanced CTL induction, OK-DCs fused with heat-treated tumor cells were most active, as demonstrated by: 1) up-regulation of multiple HSPs, MHC class I and II, CEA, CD80, CD86, CD83, and IL-12; 2) activation of CD4+ and CD8+ T cells able to produce IFN- γ at higher levels; 3) efficient induction of CTL activity specific for CEA or MUC1 or both against autologous tumor; and 4) superior abilities to induce CD107+IFN-γ+CD8+ T cells and CD154+ IFN-γ+CD4+ T cells. These results strongly suggest that synergism between OK-DCs and heat-treated tumor cells enhances the immunogenicity of FCs and provides a promising means of inducing therapeutic antitumor immunity.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Koido

Hara

Homma

et al. 2007

The Journal of Immunology

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“…Warger and colleagues (2006) have reported that 'endotoxin-free' (<0.5 U/mg) preparations of HSPC4 can stimulate DCs at concentrations greater that 50 µg/ml (containing <5 pg/ml LPS-a concentration not able to activate cells). Pre-incubation of low amounts of HSPC4 with low concentrations of LPS which are, on their own, incapable of activating DCs resulted in DC activation and an up-regulation in their T-cell stimulatory capacity (Warger et al 2006). The interpretation of these data is that there is cooperation between HSPC4 and TLR ligands and that the former amplify the effects of the latter (Warger et al 2006).…”

Section: Tuberculosis Hsp70 and Host Immunity (Tl)mentioning

confidence: 94%

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

Henderson

Calderwood

Coates

et al. 2010

Cell Stress and Chaperones

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In recent years, it has been hypothesised that a new signalling system may exist in vertebrates in which secreted molecular chaperones form a dynamic continuum between the cellular stress response and corresponding homeostatic physiological mechanisms. This hypothesis seems to be supported by the finding that many molecular chaperones are released from cells and act as extracellular signals for a range of cells. However, this nascent field of biological research seems to suffer from an excessive criticism that the biological activities of molecular chaperones are due to undefined components of the microbial expression hosts used to generate recombinant versions of these proteins. In this article, a number of the proponents of the cell signalling actions of molecular chaperones take this criticism head-on. They show that sufficient evidence exists to support fully the hypothesis that molecular chaperones have cell-cell signalling actions that are likely to be part of the homeostatic mechanism of the vertebrate.

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“…[12] Contaminating endotoxin in all proteins was removed by using the procedures by Warger et al [34] and Liu et al [35] using detergent Triton X-114, and was further eliminated with detoxi-gel endotoxin removing gel (Pierce, Rockford, IL). All materials were decontaminated of endotoxin prior to use and pyrogen-free water was used in all experiments.…”

Section: Reagentsmentioning

confidence: 99%

Treg suppress CTL responses upon immunization with HSP gp96

Liu

Qiu

et al. 2009

Eur J Immunol

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HSP gp96-based vaccines have been trialled in rodent models and, more recently, in humans. Better understanding of gp96's immunomodulatory role will help with the design of more effective strategies for treatment of cancer and infectious diseases. In this study, we monitored the activities of T cells and activation of Treg in BABL/c mice after immunization using different doses of gp96 as adjuvant. We found that co-injection of gp96 simultaneously stimulated both CTL and Treg activity. Activation of CTL at low dose was far more pronounced than Treg activation. Treg population and suppression increased with gp96 dose, eventually abrogating the T-cell response induced by immunization. Lowdose cyclophosphamide treatment could restore the T-cell responses lost after high-dose gp96 adjuvant injection by suppression of Treg activation. We further examined the effect of different doses of gp96 or N355 peptide administration on tumor rejection. Our results provide new insights into the mechanisms of gp96-mediated balance between regulatory and responder T cells, which may facilitate future development of an effective gp96-based therapeutic vaccine.Key words: CTL . gp96 . Hepatitis B virus . Treg Introduction HSP gp96, a counterpart of the cytosolic HSP90 family residing in the endoplasmic reticulum, plays important roles in the activation of innate and adaptive immunity. This molecule has the unique ability to associate with antigenic peptides from tumor, virus and intracellular bacteria. Peptides bound by gp96 are taken up by APC through cell surface receptor CD91 and can be presented by both MHC class I and MHC class II molecules [1][2][3]. In mouse models, gp96-peptide complexes have been shown to prime and induce MHC class I-restricted CTL responses by crosspresentation of peptides to MHC class I molecules. Additionally, gp96 may act as co-stimulator and activator of CD4 1 and CD8 1T cells [4], increasing cell proliferation and secretion of cytokines. The gp96 protein also induces innate immune responses. Interaction of gp96 with APC (e.g. dendritic cells) leads to maturation or enhanced function of dendritic cells [5]. Recently gp96 was demonstrated to function in the expression of both intracellular and cell surface TLR [6]. In rodent models, autologous tumor-derived gp96-peptide complexes are highly effective in the elimination of tumor burden [7,8]. Immunization of mice with gp96 complexed with specific CTL epitopes derived from various viruses has been shown to elicit virus-specific CTL or protective immunity [1,9,10]. Since gp96 has been demonstrated to act as a powerful adjuvant, clinical trials of gp96-based therapeutic vaccines have been initiated for treatment of cancer [8,11].Previous study in our lab found that gp96 and its N-terminal fragment, N355, have the ability to augment CTL responses against to hepatitis B virus (HBV). However, higher amounts of Ã These authors contributed equally to this work. 3110gp96 were detrimental to the adjuvant effect and decreased the capability of mice to generate an i...

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Interaction of TLR2 and TLR4 Ligands with the N-terminal Domain of Gp96 Amplifies Innate and Adaptive Immune Responses

Abstract: Activation of dendritic cells by ligands for Toll-like receptors (TLR) is a crucial event in the initiation

Cited by 120 publications

References 53 publications

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Synergistic Induction of Antigen-Specific CTL by Fusions of TLR-Stimulated Dendritic Cells and Heat-Stressed Tumor Cells

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

Treg suppress CTL responses upon immunization with HSP gp96

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