The stress protein gp96 is not an activator of resting rat bone marrow–derived dendritic cells, but is a costimulator and activator of CD3+ T cells

Mirza, Shabana; Muthana, Munitta; Fairburn, Barbara; Slack, Laura K.; Hopkinson, Kay; Pockley, A. Graham

doi:10.1379/csc-208.1

Cited by 15 publications

(17 citation statements)

References 67 publications

(76 reference statements)

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“…Mechanisms of action have been partially elucidated to include interaction with APC, posttranslational folding of TLR, Ag cross-presentation and activation of CTL. However, its effectiveness in immunotherapy seems to be limited in mice models [4] and in clinical trials [11,23,24]. The factors that determine the outcome of an effective immune response are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…T cells [4], increasing cell proliferation and secretion of cytokines. The gp96 protein also induces innate immune responses.…”

mentioning

confidence: 99%

Treg suppress CTL responses upon immunization with HSP gp96

Liu

Qiu

et al. 2009

Eur J Immunol

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“…Although this sequence of events is commonly accepted, we have been unable to demonstrate that gp96 influences the phenotype, function, or activation status of rat bone marrow-derived DCs (Mirza et al, in press). We have also shown that it does not bind to these cells in a receptor-mediated manner; rather, it is internalized by pinocytosis (Mirza et al 2006).…”

Section: Discussionmentioning

confidence: 80%

“…DCs can subsequently present antigenic peptides that are derived from pinocytosed exogenous material to T cells (reviewed in Norbury [2006]). Given that gp96 does not activate DCs (Mirza et al 2006), then the presentation of gp96-associated peptides to responding T cells by APCs that have endocytosed gp96 would occur in the absence of essential costimulatory signals-the consequence of which could be the induction of T-cell populations with the capacity to attenuate inflammatory disease. It is also possible that gp96 directly influences T-cell populations, and in this regard, we (Mirza et al 2006) and others (Banerjee et al 2002) have demonstrated that gp96 can bind to T cells and act as a costimulatory molecule that promotes the secretion of anti-inflammatory type 2 cytokines.…”

Section: Discussionmentioning

confidence: 99%

Administration of the stress protein gp96 prolongs rat cardiac allograft survival, modifies rejection-associated inflammatory events, and induces a state of peripheral T-cell hyporesponsiveness

et al. 2007

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High-dose gp96 has been shown to inhibit experimental autoimmune disease by a mechanism that appears to involve immunoregulatory CD4 ϩ T cells. This study tested the hypothesis that high-dose gp96 administration modifies allograft rejection and associated inflammatory events. Wistar cardiac allografts were transplanted into Lewis recipient rats and graft function was monitored daily by palpation. Intradermal administration of gp96 purified from Wistar rat livers (100 g) at the time of transplantation and 3 days later significantly prolonged allograft survival (14 vs 8 days in phosphate-buffered saline [PBS]-treated recipients; P ϭ 0.009). Rejected allografts from gp96-treated animals were significantly less enlarged than allografts from their PBS-treated counterparts (2.8 vs 4.3 g; P Ͻ 0.004). Gp96 was also effective when administered on days 1 and 8 (13 vs 7 days), but not if it was derived from recipient (Lewis) liver tissue or administered on days 0, 3, and 6. In parallel studies, CD3 ϩ T cells from gp96-treated untransplanted animals secreted less interleukin (IL)-4, IL-10, and interferon (IFN)-␥ after in vitro polyclonal stimulation than CD3 ϩ T cells from PBS-treated animals. Gp96 administration might therefore influence the induction of immunity to coencountered antigenic challenges and inflammatory events by inducing what appears to be a state of peripheral T-cell hyporesponsiveness.

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“…Third, in vitro-cultured dendritic cells have been shown to adopt a tolerizing phenotype, rather than a mature or activated phenotype, in the presence of HSPs 10,11 . Fourth, in experimental models of autoimmunity and of tissue or tumour transplants, immunization with HSPs was shown to lead to the induction of regulatory T cells, which suppressed disease or transplant rejection [12][13][14][15][16][17][18][19] .…”

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confidence: 99%