Abstract
In addition to their conventional chaperon activity, numerous studies have reported that heat shock protein 70 (HSP0) exhibit immune properties and especially the capacity (i) to induce the presentation and cross-presentation of associated or client proteins and, (ii) to control myeloid cell activation. Several studies were focused on the identification of HSP70-binding elements that contribute to their immune properties. A general consensus was reached on the nature of the endocytic receptors involved in the internalization of extracellular HSP70 with belong, for most of them, to the innate immunity receptor family. However, the nature of signaling receptors recruited by HSP70 remains unclear, because the stimulatory versus regulatory properties of HSP70 remains a subject of debate. Nevertheless, these unique immune properties allowed developing innovative prophylactic and therapeutic vaccines, especially in the treatment of cancers and chronic viral infections. Although HSP70 constitute potent vaccine vehicles in different preclinical models, clinical studies remain disappointing. The fact that the immune properties of HSP70 have not been totally clarified may explain their relative efficacy in human. In this review are presented the main immune properties of HSP70 related to the HSP70-binding elements identified to date, and discuss our current knowledge on their intrinsic immune properties.
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Introduction
Heat shock proteins (HSP) are involved in 3D-folding of newly synthesized proteins and protect them against endogenous and exogenous assaults. Besides their classical biochemical properties, several studies have demonstrated that HSP70, one of the largest and highly conserved family of HSP, exhibit intrinsic immune properties. The potential immune properties of HSP70 were first hypothesized in the 1970s by showing that proteins with an apparent molecular weight of 70 kDa and isolated from tumor cells may induce a protective immune response in vivo, in the absence of adjuvant. Thereafter, a huge quantity of studies aimed at deciphering, in vivo and in vitro, the biological mechanisms involved in the immune properties of HSP. Most of the immune properties of HSP were first elucidated for gp96 (HSP90B1), a member of the HSP90 family, and thereafter for HSP70. One of the most remarkable immune properties of HSP70 is their ability to mediate the cross-presentation of exogenous antigens and to initiate protective antitumor immune responses. In agreement with the cross-presentation process, HSP70 have been shown to interact with different immune receptors, especially innate receptors. However, the exact nature of the endocytic and signaling receptors engaged by HSP70, as well as whether HSP70 exhibit stimulatory or regulatory immune properties, remain a subject of debate. Nevertheless, and whatever the mechanism involved, HSP70 constitute interesting vehicles to induce, in vivo, antigen-specific cytotoxic responses. This review thus addresses the immune properties of HSP70, with a focus on the innate immune receptors engaged, and the consequences on vaccine strategies.
HSP70 Family of Chaperones
Common Features of HSP70
The 70 kDa heat shock proteins (HSP70s) constitute a family of highly conserved proteins that are ubiquitously expressed in prokaryotes and eukaryotes. Prokaryotes express three HSP70 proteins (DnaK, HscA (Hsc66), and HscC (Hsc62)) whereas eukaryotes express several HSP70s. As an example, the human family comprises 13 proteins, that differ from each other by their amino acid sequence, their levels of expression and their localization (Radons 2016). The mostly expressed inducible human HSP70s are Hsp70–1 (encoded by the HSPA1A gene) and Hsp70–2 (HSPA1B); these two genes are closely located in the genome (Brocchieri et al. 2008). In line with the topic of this review, it is important to mention human HSP70–14 (also referred to as Hsp70L1), a stress-induced HSP identified in dendritic cells, exhibits potent immunostimulatory properties by favoring Th1 responses (Wan et al. 2004). Interestingly, the levels of HSP0L1 are elevated in some tumors (Yang et al. 2015).
HSP70s display a common functional domain structure: (i) a 44 kDa N-terminal nucleotide binding domain (NBD) that binds and hydrolyzes ATP, (ii) a middle protease-sensitive domain and, (iii) a 28 kDa C-terminal substrate-binding domain (SBD) that can interact with 6–9 amino acid-long peptides; SBD has preferential affinity for neutral and hydrophobic amino acids. HSP70s are monomeric chaperons that participate, in physiological situations, to the folding of neo-synthesized proteins, to their transport and to the assembly of multi-protein complexes. The binding/release of polypeptides is dependent on the ATPase activity: the ADP- and ATP-bound states favor peptide binding and release, respectively. HSP70s also regulate the activity of proteins and prevent their aggregation. Indeed, HSP70s exhibit an « unfoldase » activity, meaning that they recognize unfolded or aggregated proteins and unfold them before native refolding (Radons 2016). The expression of HSP70s is strongly upregulated by cellular stress, such as heat, toxic chemicals (such as heavy metals), ischemia, irradiations, infection, inflammation and nutrient deprivation. In stressed cells (induced by endogenous or exogenous challenges), HSP70s promote cell survival and allow cells to restore cellular homeostasis.
HSP70s act as anti-apoptoti proteins via their capacity to prevent mitochondrial translocation and activation of Bax (Yang et al. 2012) and to inhibit assembly of the death-inducing signaling complexes (Guo et al. 2005). HSP70s also inhibit the activity of different pro-apoptotic molecules (such as Apaf-1, AIF and caspase 3) (Beere et al. 2000; Ravagnan et al. 2001). HSP70s can protect cells against apoptosis induced by endoplasmic reticulum stress via their interaction with the ER stress sensor protein IRE1α (Wei et al. 2013).
Intracellular, Membrane and Extracellular HSP70
As the other HSP, members of the HSP70 family are mainly expressed in intracellular compartments, including cytosol, endoplasmic reticulum (such as binding immunoglobulin protein (BiP) or Grp78) and mitochondria (mtHsp70 or Grp75), to exert their chaperon activities. Nevertheless, HSP70s can be expressed at the membrane surface or present, in a soluble form, in different biological fluids. Membrane HSP70s (mHSP70) accumulate at the surface of infected and tumor cells but not living cells (Multhoff et al. 1995; Multhoff and Hightower 1996; Poccia et al. 1996). Different mechanisms have been proposed to explain the membrane relocalization of proteins devoid of secretion signals, such as the release of secretory granules (Evdonin et al. 2004; Mambula and Calderwood 2006a, b) and of exosomes (Gastpar et al. 2005; Lancaster and Febbraio 2005). The apparently « passive » accumulation of HSP70 at the cell membrane appears similar to the one reported for other intracellular molecules, such as PTX3 (Jaillon et al. 2009), or danger molecules, such as histones and nucleic acids (Cunin et al. 2016) that have also been reported to accumulate at the surface of stressed cells. Accordingly, mHSP70 may have an important role in the recognition of stressed and tumor cells by innate immune cells (Multhoff 2007; Radons and Multhoff 2005). Based on their biochemical properties, one can suspect that mHSP70 are associated to membrane proteins; however, to date, the nature of these putative mHSP70-associated molecules remains unknown.
Another explanation should be that extracellular HSP70s may bind to altered molecules, such as oxidized proteins, that are present at the surface of stressed cells, in a way similar to the one of bridging molecules (Henson 2017). HSP70s can be released by numerous cell types in response to various stimuli (Campisi and Fleshner 2003). Different ways of secretion of HSP70 have been described:
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A passive release by necrotic cells (Fleshner and Johnson 2005),
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The disruption of HSP70-containing secretory vesicles/exosomes released via a non-classical secretion pathway (MacKenzie et al. 2001) and,
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A release via the secretion of lysosomal endosomes (Baraldi et al. 2004; Mambula and Calderwood 2006b).
HSP70s can be used as biomarkers. As an example, mHSP70s are considered as selective markers of aggressive tumors. Circulating HSP70 have been proposed as biomarkers of inflammation in healthy subjects (Gehrmann et al. 2014a; Marotta et al. 2007). HSP70s have been detected in the serum of patients suffering from cancer or chronic infection (Pockley et al. 2014) and are proposed as biomarkers of tumor outcome after treatment (Gehrmann et al. 2014a, b). These data suggest that the immune properties of HSP70s may depend not only on the nature of the chaperoned peptides but also on their localization. Indeed, membrane and extracellular HSP70 may influence the nature and amplitude of signals delivered to immune cells present in the close vicinity or at distance.
HSP70 Induce Protective Immune Responses Against Tumors and Microbial Pathogens
Most of the studies on the use of HSP70s as vaccine vehicles have been performed in preclinical models of tumor growth. Nevertheless, and based on their vaccine potential, HSP70 have been also used for the induction of protective immune responses against microbes. In this paragraph, we focus on the antitumor immune responses induced by HSP70s.
HSP70s Mediate Antigen Presentation and Cross Presentation
The pioneering studies by the group of PK Srivastava demonstrated that tumor-derived gp96 initiate protective tumor-specific CTL responses, suggesting that HSP may act as major tumor-rejection antigens (Suto and Srivastava 1995; Tamura et al. 1997). This capacity to induce protective antitumor immune responses has been extended to other HSP families, especially HSP60 and HSP70 families (Castellino et al. 2000). The capacity of HSP70s to induce protective antitumor immune responses was mainly reported in both prophylactic and therapeutic murine models of tumor development (reviewed in (Srivastava 2002). Moreover, HSP70s also induce cross-presentation of human tumor antigens (Castelli et al. 2001; Milani et al. 2002; Noessner 2006; Noessner et al. 2002), the rationale for their use in tumor vaccines in humans. In fact, numerous studies have clearly demonstrated that the specificity of the anti-tumor immune response was determined by the chaperoned peptides (Binder and Srivastava 2005; Ishii et al. 1999; Suto and Srivastava 1995). Biochemical analysis have shown that peptides associated to HSP70 are very diverse, deriving from self-proteins, tumor, microbial or minor histocompatibility antigens (Srivastava 2002). As an example, HSP70s isolated from melanoma cell lines can chaperon peptides derived from the tumor antigens Mart-1, gp100, Trp2 and gp100 (Castelli et al. 2001; Noessner et al. 2002).
According to the classical view of antigen presentation, antigen-derived peptides are presented into the MHC class I (MHC-I) and MHC class II (MHC-II) molecules of antigen-presenting cells (APC) to epitope-specific T cell receptors (TCR) expressed by CD8+ and CD4+ T cells, respectively. This interaction is the basis of the antigen-specificity of the adaptive immunity. Although different myeloid cells are able to present antigens to T cells (such as macrophages and neutrophils), dendritic cells are the only APC able to prime naive T cells and to initiate immune responses (Banchereau et al. 2000; Cella et al. 1997).
The process by which some exogenous antigens are endocytosed by APCs, gain access to the MHC class I pathway, and stimulate CD8+ T cells is called cross-presentation (Heath and Carbone 2001; Yewdell et al. 1999). Indeed, the classical view of antigen presentation claimed that exogenous antigens endocytosed by APC are mainly loaded into the MHC-II molecules for recognition by CD4+ T cells, while, in contrast, endogenous antigens (self and viral proteins) are loaded in the MHC-I molecules for recognition by CD8+ T cells. Antigen cross-presentation has revolutionized our view of the induction of antigen-specific immune responses and allowed to propose « conventional » vaccine approaches for the treatment of cancers. The HSP-mediated antigen cross-presentation is dependent on three essential mechanisms:
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A receptor-mediated internalization of the antigens by professional APCs, especially dendritic cells,
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The functional maturation and activation of professional APC, rendering them able to prime naive T cells and,
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An intracellular trafficking allowing exogenous antigens/peptides to get access to the MHC-I presentation pathway.
One of the most important, and also most debated immune property of HSP, is their capacity to activate APCs. Indeed, the priming of CD8+ T cells by exogenous antigens requires that APC are fully activated (Banchereau et al. 2000), a status that may require CD4+ T cell help (Heath and Carbone 1999). The cross-presentation of an antigen by non-activated dendritic cells maintains or induces antigen-specific tolerance; this process is referred to as cross-tolerance. Ideally, the induction of functional CD8+ T cell responses against exogenous antigens may require both antigen cross-presentation in MHC-I molecules to CD8+ T cells and presentation in MHC-II molecules to CD4+ T cells. In agreement with the classical view of antigen presentation, HSP70 also induce antigen-specific CD4+ T cell activation, as evidenced by the induction of humoral immune responses and the interaction of microbial HSP70 with HLA-DR and their peptide fragments (Haug et al. 2007). Moreover, HSP70 chaperon both MHC-I and MHC-II epitopes (Stocki et al. 2010; 2011).
Potential Immunomodulatory Roles of Extracellular HSP70
The fact that (i) HSP70s mediate the cross-presentation of chaperoned peptides and (ii) that the cross-presentation requires receptor-mediated internalization of the peptide/chaperone complex, suggest that HSP70s have to be released in the extracellular milieu (Stocki and Dickinson 2012). According to their capacity to induce effective immune response, several studies reported that HSP70s are immunostimulatory molecules and, more interestingly, can induce the maturation and activation of dendritic cells, rendering them fully functional (reviewed in (Kuppner et al. 2001; Milani et al. 2002; Srivastava 2002). The term chaperokine was attributed to HSP to define this unique capacity of chaperons to activate immune cells (Asea et al. 2000). However, the intrinsic potential of HSP70s to activate APC remains a subject of debate (Borges et al. 2012) (see paragraph 5).
HSP70-Binding Elements
Antigen cross-presentation requires that exogenous antigens are internalized via endocytic receptors [3, 4]. Accordingly, HSP70s bind to dendritic cells and macrophages (Arnold-Schild et al. 1999; Todryk et al. 1999; Wassenberg et al. 1999) before being internalized in a receptor-dependent manner (Arnold-Schild et al. 1999; Basu et al. 2001; Binder et al. 2000; Castellino et al. 2000; Singh-Jasuja et al. 2000; Sondermann et al. 2000; Wassenberg et al. 1999). Most if not all HSP70-binding elements identified are innate immune receptors. These results are in agreement with the fact that, in an immunological point of view, extracellular HSP70 can be viewed (or detected) as a danger signal (modified self) released by altered/dying cells. These motifs are detected by the innate immune system.
By opposition to the adaptive immunity, innate immunity is defined as a non-antigen specific system. It is involved in numerous processes, such as antimicrobial activity, induction and resolution of inflammation, maintenance of tissue homeostasis and wound healing. The innate immune system includes a large variety of molecular and cellular actors, such as epithelial barriers, numerous soluble molecules (including the complement system) and innate lymphoid and myeloid cells. The most remarkable characteristic of innate immune cells is their capacity to discriminate self from non self (microbes) and altered or modified self (such as the detection of biochemical modification of cell surface molecules). The recognition of non self and modified self is mediated by a restricted number of molecules (compared to the TCR and BCR repertoires) called pattern recognition molecules (PRM); this term is now preferred to the ancient nomenclature pattern-recognition receptor (PRR). PRM recognize microbial moieties called pathogen-associated molecular patterns (PAMPs) and motifs expressed by altered self and called danger-associated molecular patterns (DAMPs). Remarkably, a same PRM can detect different PAMPs and DAMPs and exhibiting diverse biochemical characteristics (such as nucleic acids, lipids, proteins or glucids). Innate immune cells also orchestrate the adaptive immune response via the production of soluble immune mediators (cytokines and chemokines) and the priming/activation of antigen-specific lymphocytes, thanks to the antigen-presenting functions of myeloid cells.
PRM can be classified into three families, based on their functions: (i) endocytic receptors, involved in ligand recognition and internalization, (ii) signaling receptors, involved in ligand-induced cell activation and (iii) bridging molecules (also called opsonins), that bind to and favor the recognition of extracellular ligands by innate cells. To date, and except some individual cases, most of the HSP70-binding elements are endocytic and/or signaling PRM.
Endocytic Receptors
CD91
CD91 was the first HSP-binding element identified, initially as a gp96 receptor (Binder et al. 2000). CD91 was then reported as a receptor for human HSP70s on macrophages (Basu et al. 2001). CD91, also known as the α2 macroglobulin (A2M) receptor, low density lipoprotein receptor-related protein 1 (LRP1) or apolipoprotein E receptor (APOER), is an endocytic and signaling receptor belonging to the lipoprotein receptor family. CD91 is expressed by numerous cell types, including hepatocytes, fibroblasts, keratinocytes, smooth muscle cells and myeloid cells (Herz and Strickland 2001). CD91 is a multimeric receptor consisting of a 420 kDa α subunit, a 85 kDa β subunit and a 39-kDa associated molecule. CD91 binds to the activated form of α2M, a soluble molecule that binds to and inhibits a wide variety of proteinases and growth factors. CD91 is also suspected involved in lipid metabolism and can bind, in addition to activated A2M, tissue-specific plasminogen-activator−inhibitor complex and urokinase-PAI1 complex.
The identification of CD91 as an HSP-binding structure was mainly based on competitive binding assays with the CD91 ligand A2M and with a neutralizing anti-CD91 mAb. The role of CD91 in HSP70-mediated antigen presentation to CD4+ and CD8+ T cells was confirmed by several independent studies (Fischer et al. 2010; Salimu et al. 2015; Tobian et al. 2004a).
Scavenger Receptors
Scavenger receptors represent a family of non-related cell-surface glycoproteins that recognize a large repertoire of ligands, ranging from bacteria and yeast to self (native proteins) and modified-self such as oxidized LDL (Ox-LDL) and apoptotic cells (reviewed in (Yamada et al. 1998; Yu et al. 2015)). Some scavenger receptors can also bind chemically modified LDL (acetylated LDL) that constitutes reliable tools in identifying HSP-binding elements, especially as binding competitors. Scavenger receptors thus represent an important family of endocytic PRM through their ability to bind endogenous and exogenous danger molecules (Jeannin et al. 2008). Different studies reported that scavenger receptor-binding molecules, such as modified LDL (OxLDL or AcLDL), apoliprotein B, fucoidan and poly[IC], inhibited the binding of HSP70 to human APCs, suggesting that these PRM are the main cell surface HSP70 binding elements on human APCs (Delneste et al. 2002; Facciponte et al. 2007; Theriault et al. 2006; Theriault et al. 2005).
The first identified HSP70-binding scavenger receptors was SR-E1. Initially identified as an Ox-LDL receptor expressed by endothelial cells; this molecule, also known as LOX-1 or CLEC8A (C-type lectin domain family 8 member A), binds multiple ligands, including advanced glycation end products (AGE), activated platelets, and apoptotic cells. SR-E1 also binds exogenous ligands, such as virus and bacteria. In addition to endothelial cells, SR-E1 is constitutively expressed by macrophages and dendritic cells (Delneste et al. 2002). By using a collection of scavenger receptor-expressing CHO cells, we have identified SR-E1 as one of the main HSP70-binding element on human macrophages and dendritic cells. Interestingly, the in vitro and in vivo cross-presentation of an antigen coupled to HSP70 is dependent on SR-E1 internalization (Delneste et al. 2002). Finally, the in vivo targeting of an exogenous antigen to SR-E1, by coupling to an anti-SR-E1 antibody, induced an antigen-specific CD8+ T cell response (Delneste et al. 2002).
SR-E1 also exhibits features of C-type lectins (Sawamura et al. 1997) which represent another important family of highly conserved PRM. Several studies have underlined the important role played by C-type lectins in mediating antigen cross-presentation, both in vitro and in vivo. Among these PRM, one can mention CD205 (DEC205) (Bozzacco et al. 2007) and CD209 (DC-SIGN) (Garcia-Vallejo et al. 2013). However, no binding of HSP70s to some other C-type lectins, such as CD209 (Theriault et al. 2005) and CLEC7A (dectin-1), was reported so far. A binding of HSP70 family members was also reported to other scavenger receptors:
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SR-A1 (Facciponte et al. 2007); SR-A1 (CD204) is a 220–250 kDa trimeric molecule that shares a collagen-like domain, essential for ligand binding. SR-A1 binds numerous endogenous and exogenous ligands, such as AGE products, as well as microbes and microbial moieties.
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SR-B1 (Fischer et al. 2010). Also known as CD36, platelet glycoprotein 4, fatty acid translocase (FAT) or glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV), SR-B1 preferentially accumulates in caveolae. SR-B1 bind modified LDL (OxLDL and AcLDL), unmodified low density lipoproteins (LDL), very low density lipoproteins (VLDL) and apoptotic cells. SR-B1 is a heavily N-glycosylated protein with the C-terminal cytoplasmic tail that interacts with the multisubunit adaptor protein PDZK.
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SR-F1 (Facciponte et al. 2007; Gong et al. 2010; Theriault et al. 2006). Also known as SREC-I, SR-F1 mediates the internalization of OxLDL (as well as AcLDL). SR-F1 can also interact with SREC-2, a homologous of SR-F1, via its extracellular domain; although the role played by this heterophilic interaction remains unclear, it is suppressed by SR-F1 ligands.
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SR-H1 (Theriault et al. 2006). Also known as FEEL-1, CLEVER-1 or stabilin-1 (STAB1), SR-H1 binds AcLDL, AGEs as well as Gram-negative and Gram-positive bacteria (Adachi and Tsujimoto 2002; Tamura et al. 2003).
These endocytic receptors are involved in the internalization and presentation of associated antigens to CD4+ and CD8+ T cells (Facciponte et al. 2007; Gong et al. 2010).
CD40
In 2001, the group of T Lehner reported a very elegant study showing that CD40 is a binding and uptake receptor for Mycobacterium tuberculosis HSP70 (MtbHSP70), but not human HSP70 (Binder 2009; Wang et al. 2001). CD40, a membrane molecule belonging to the TNF receptor superfamily (TNFRSF5), is constitutively expressed by APCs, including macrophages, dendritic cells and B lymphocytes. Triggering CD40 on myeloid cells induces the production of inflammatory cytokines. The engagement of CD40 on B cells induces their maturation, antibody isotype switching, and their differentiation into plasma cells. The ligand of CD40 is a member of the TNF superfamily, TNFSF5, also called CD40 ligand (CD40L) or CD154. CD154 is mainly expressed by activated CD4+ T cells and acts as a costimulatory molecule for B cells and myeloid cells; the engagement of CD154 participates to the T cell priming process.
A subsequent study by the same group showed that the binding of MtbHSP70 to the extracellular domain of CD40 was localized in the N-terminal nucleotide-binding domain in its ADP (peptide-binding) state (Becker et al. 2002). To date, CD40 has been mainly reported as a signaling receptor (reviewed in (Banchereau et al. 1994); its role in myeloid cell activation by HSP70 is discussed in the paragraph “Signaling receptors”.
C-type Lectins
As mentioned above, HSP70 can bind to the C-type lectin/scavenger receptor SR-E1 which is constitutively expressed on myeloid cells. Studies have also reported that HSP70 can bind to the C-type lectin CD94 (Gross et al. 2003a; Moser et al. 2002). CD94/NKG2 is a family of receptors mainly expressed on natural killer (NK) cells and a subset of CD8+ T cells. The consequences of HSP70 binding to CD94 on the biology of NK cells is detailed in the paragraph 4.
Signaling Receptors
HSP70 can efficiently cross-prime naive T cells, a process that required an optimal activation of APCs. However, some of the endocytic receptors identified are not signaling molecules, such as SR-E1, suggesting that signaling receptors are recruited by HSP70s. Numerous studies were thus focused on identifying HSP70 signaling receptors.
TLRs
Through their pivotal role in the activation of myeloid APCs, members of the Toll-like receptor (TLR) family are crucial in the initiation of innate and adaptive immune responses. The induction of in vivo immune responses by HSP70 suggested that they can activate myeloid cells and members of the TLR family rapidly emerged as candidate molecules. TLRs are type I integral membrane glycoproteins belonging to the IL-1 receptor (IL-1R) superfamily. TLR and IL-1R have a conserved region of ≈ 200 amino acids in their cytoplasmic domain, known as Toll/IL-1R (TIR) domain. The TIR domain is required for the intracellular signaling induced by TLR ligands. TLR can sense a large variety of microbes and microbial moieties, as well as host motifs. They are localized either at the cell surface or in endosomes where there are specialized in detecting microbes or nucleic acids, respectively. After ligand binding, TLRs dimerize and undergo a conformational change required for the recruitment of downstream signaling molecules that include the adaptor molecule myeloid differentiation primary-response protein 88 (MyD88), IL-1R-associated kinases (IRAKs), TGFβ-activated kinase (TAK1), TAK1-binding protein 1 (TAB1), TAB2 and TNF-receptor-associated factor 6 (TRAF6). The engagement of TLRs generates potent activation signals for myeloid cells, as evidenced by the production of numerous pro-inflammatory cytokines, chemokines and interferons (IFNs). TLR agonists also induce the maturation of dendritic cells, a process required for naïve T cell priming. TLR agonists may also participate to the activation of innate and conventional lymphoid cells.
Asea et al. reported that TLR2/TLR4 are involved in the activation of myeloid cells by HSP70 (Asea et al. 2000, 2002), as evidenced by the production of the inflammatory cytokines IL-1β, TNFα and IL-12, and an elevated expression of the costimulatory molecule CD86. The HSP70-induced signaling was mediated via the MyD88/IRAK/NF-kB signaling pathway. The role played by TLR4 in the activation of dendritic cells and in the induction of a Th1 response by HSP70s was confirmed by others (Fang et al. 2011).
TLR4 was initially described as an element of the multimeric LPS receptor which includes, in addition to TLR4, the binding elements CD14 and LBP and the accessory molecule MD2. Accordingly, the activation of APCs induced by HSP70 requires CD14, in addition to TLR4; however, no data supported a direct binding of HSP70 to CD14 (Asea et al. 2000; Moroi et al. 2000). In line with the capacity of HSP70 to signal via TLR2/TLR4, several endogenous ligands have reported to bind to these molecules, including, in addition to other HSP (HSP60, HSP96), HMGB1, surfactant protein D (SP-D), fibrinogen, fibronectin, and hyaluronic acid (Bryant et al. 2015).
CD91
CD91 is phosphorylated in response to HSP, triggering signaling cascades that ultimately lead to the activation of NF-κB (Pawaria and Binder 2011). The stimulatory function of CD91 was confirmed in another study showing that the proliferation and cytokine production by CD4+ T cells in response to APC pulsed with complexes between HSP70 and antigenic peptides was inhibited by CD91 siRNA (Fischer et al. 2010). Accordingly, the CD91 ligand A2M acts as an adjuvant to prime CD8+ T cells in vivo (Kropp et al. 2010).
CD40
MtbHSP70 induced a CD40-mediated production of numerous cytokines and chemokines, such as CCL3 (MIP1α) involved in the recruitment and activation of polymorphonuclear cells, CCL4 (MIP1β) chemotactic for numerous immune cells and, CCL5 (RANTES), chemotactic for T cells. This property can be explaind by the adjuvanticity of MtbHSP70 (Wang et al. 2001). The binding of MtbHSP70 to CD40 induces an intracellular signaling via p38, associated with the internalization of the complex HSP70-CD40. P38 is a transduction molecule involved in the signaling cascade downstream CD40 that is involved in the production of pro-inflammatory cytokines, such as TNFα and IFNγ (Pullen et al. 1999).
CCR5
C-C chemokine receptor type 5 (CCR5), also known as CD195, acts as a receptor for the C-C chemokines CCL3, CCL4, and CCL5, three chemokines induced by MtbHSP70. CCR5 is mainly involved in the attraction of T cells in specific tissues and organs. The signaling via CCR5 induces dendritic cell activation and aggregation and participates to the formation of the immune synapse between dendritic cells and T lymphocytes (Floto et al. 2006). The binding of MtbHSP70 to CCR5 induces a Ca2+ signaling and the engagement of CCR5 participates in the generation effector immune responses (MacAry et al. 2004). In this study, the authors showed that the activation by MtbHSP70 was not dependent on TLR signaling.
Cooperation Between Endocytic and Signaling Receptors
Except some HSP70-binding elements, such as CD91 and CD40 which can act as both endocytic and signaling receptors, several studies suggest that the activation of innate immune cells by HSP70 requires cooperation between an endocytic receptor and a signaling receptor. This mechanism of interaction is observed in several examples of innate immune cell activation by non self and altered self. Nevertheless, in most cases, this model is supported by indirect in vivo experiments using HSP70 as a vaccine carrier molecule. As an example, Gong et al have demonstrated that the induction of antitumor immunity by HSP70 isolated from tumor-dendritic cell fusions is dependent on functional SR-F1 and TLR2/TLR4 expression by dendritic cells (Gong et al. 2009). In a similar manner, we have reported that targeting in vivo a vaccine antigen to SR-E1 is not sufficient to induce a protective antitumor response and that protection was only observed when antigen targeting was associated with the use of a TLR-activating adjuvant (Delneste et al. 2002). Interestingly, Mizukami et al showed that the cross-priming capacity of HSP70s was mediated by a TLR-independent mechanism, while the MyD88/IRAK signaling was required to induce tumor rejection (Mizukami et al. 2012).
Hsp70 in the Regulation of Innate Immune Cell Activation
HSP70s, as other members of the HSP superfamily, induce antigen-specific immune responses, in vitro and in vivo, a process that requires activation of APCs. As a consequence, several studies have reported that HSP70 induce the activation of innate immune cells, and especially myeloid cells.
Activation of Myeloid Cells
In addition to their role as sentinels of the innate immune system, macrophages and dendritic cells also act as professional antigen-presenting cells. Although macrophages are only able to present antigens to memory T cells, dendritic cells have the unique capacity to prime naive T cells. HSP70s can induce not only the cross-presentation but also the presentation of chaperoned peptides and coupled antigens to CD4+ and CD8+ T cells. The fact that HSP70s induce protective immune CD4+ and CD8+ T cell responses suggests that they are able to activate APCs. It is important to mention that antigen presentation and cross-presentation induced by HSP70s involve the same endocytic and signaling receptors. As an example, CD91 and scavenger receptors are involved in the activation of antigen-specific memory CD4+ T cells (Fischer et al. 2010). The role of HSP70 in the induction of CD4+ T cells has been also reported by other studies (Mycko et al. 2004; Tobian et al. 2004a, b; Wang et al. 2006).
As mentioned above, extracellular HSP70s induce the production of pro-inflammatory cytokines (TNFα, IL-1β, IL-6) and C-C chemokines by myeloid cells (Asea et al. 2000, 2002; Redzovic et al. 2015; Wang et al. 2001). HSP70s also induce the production of IL-12 (Vabulas et al. 2002), a pro-Th1 cytokine, and of IL-15 (Redzovic et al. 2015), a cytokine involved in the activation of innate and adaptive cytotoxic lymphoid cells, as well as type I IFNs by plasmacytoid cells (Jacquemin et al. 2017). The activation of myeloid cells is also associated with an increase of expression of MHC-II and of the costimulatory molecules CD40, CD80 and CD86 (Asea et al. 2002; Fang et al. 2011; Wang et al. 2002) which provide stimulatory signals required for optimal T cell activation.
Interestingly, HSP70s were reported to induce dendritic cell maturation (Kuppner et al. 2001; Vabulas et al. 2002; Wang et al. 2002), a process required to prime naive T cells against neo-antigens. Importantly, the capacity of HSP70 to activate and induce the maturation of dendritic cells supports their ability to generate immune responses in vivo, in the absence of adjuvant (Srivastava et al. 1998). As a consequence of their dendritic cell-stimulatory activity, HSP70s have been reported able to convert T cell tolerance to autoimmunity in vivo, in a murine model of model of autoimmune diabetes (Millar et al. 2003). Studies also reported that an intratumoral infusion of HSP70 increase the infiltration of cytotoxic lymphoid and the production of IFNγ (Shevtsov et al. 2014).
Activation of Innate Lymphoid Cells
NK cells are innate lymphoid cells that play a pivotal role in the destruction of virus-infected cells and tumoral cells. Their activation is dictated by a delicate balance between stimulatory and regulatory signals (Narni-Mancinelli et al. 2013). The overexpression of HSP70 by tumor cells has been reported as a marker of tumor immunogenicity (Clark and Menoret 2001) and in vivo studies showed that tumors secreting HSP70s display increased immunogenicity, with induction of strong and specific CTL responses (Massa et al. 2004). Interestingly, CD94+ CD3- NK cells can recognize and kill membrane HSP70-positive tumor cells in a granzyme-dependent manner (Moser et al. 2002; Multhoff et al. 1995). The interaction of HSP70 with CD94 was demonstrated by competitive binding experiments (Gross et al. 2003a, b).
Moreover, in the absence of HLA-E expression, the activation of NK cells with the HSP70 peptide TKD render them cytotoxic against target cells (Bottger et al. 2012; Gross et al. 2008). More intriguingly, Massa et al reported that the interaction of HSP70 with NK cells may also participate in the initiation of antigen-specific T cell responses. More precisely, the authors demonstrated that the adjuvant activity of HSP70 requires NK cells at the site of dendritic cell-HSP70 interaction whereas its ability to induce antigen cross-presentation of chaperoned peptides is independent of NK cells (Massa et al. 2005). A recent study reported that HSP70-positive exosomes derived from genotoxic drug-treated tumor cells induce the production of cytokines by CD56high NK cells in a TLR2-dependent manner (Vulpis et al. 2017).
The Immune Properties of HSP70: An Unsolved Mystery
Innate immunity receptors act as immune sensors able to discriminate self from non-self and modified self. In most cases, the elimination of modified self does not activate immune cells, maintaining tissue homeostasis and preventing the initiation of a potentially harmful autoimmune response. Internalization without recruitment of a signaling receptor may lead to tolerance, as reported for the internalization of apoptotic cells. As an example, the interaction of TSP-1 with CD91 and CD36, two HSP70-binding elements, may participate to the tolerogenic status of dendritic cells after apoptotic cell phagocytosis (Poon et al. 2014). In agreement with these studies, the presentation of apoptotic-cell-derived antigens requires the presence of a TLR agonist in the same cargo as that of apoptotic cells (Blander and Medzhitov 2006).
However, most of innate endocytic receptors also recognize non self (microbes and microbial moieties) that induce a huge activation of immune cells. The concept of cooperation between endocytic and signaling receptors has thus emerged to explain this dichotomy. Innate cell activation induces the recruitment of signaling PRM after the binding of ligands to the endocytic receptor. In a similar manner, HSP70 endocytosis precedes signaling in myeloid cells (Kuppner et al. 2001; Moroi et al. 2000). In contrast to early apoptotic cells, necrotic cells induce a pro-inflammatory response, thanks to the release of stimulatory endogenous molecules called alarmins. These alarmins, such as HMGB1, IL-33 and ATP, activate immune cells and participate in the initiation of antigen-specific immune responses. Based on the studies showing that HSP70s activate APCs, it has been proposed that HSP70 may be considered as a danger signal. However, other authors refute to classify HSP70 as a DAMP (van Eden et al. 2012). Indeed, circulating HSP70 are detected in the serum of healthy subjects, without signs of inflammation. Moreover, different studies argue that the stimulatory activities of HSP70s are associated to the presence of contaminating molecules in HSP70 preparation.
Do HSP70 Interact with a Limited Number of Receptors?
To date, HSP70s have been reported to interact with a large variety of immune receptors. However, and even though most studies concur to recognize that HSP70 are able to induce antigen (cross) presentation, different studies refuted the HSP70-binding capacity to some receptors. Although this initial study was confirmed by subsequent studies (Binder and Srivastava 2004; Salimu et al. 2015), authors contested the fact that CD91 may be considered as an HSP-binding structure, either by using CD91null cells or by demonstrating that the binding of HSP to CD91 was not altered by the conventional CD91 ligand activated α2 macroglobulin (A2M*) or the CD91 antagonist molecule, receptor-associated protein (RAP) (Berwin et al. 2002). Moreover, although highly expressed on macrophages, the expression of CD91 is very low on dendritic cells, suggesting that its role in in vivo T cell priming should be marginal. Moreover, Theriault et al. reported that scavenger receptors, but not CD40 and CD91, are the main HSP70-binding elements (Theriault et al. 2005). In a similar manner, Bendz et al have shown that the cross-presentation capacity of different dendritic cell subsets was equivalent, irrespective of the level of CCR5 expression (Bendz et al. 2008).
HSP70 are endogenous molecules that, theoretically, cannot activate APCs. Nevertheless, several studies reported that HSP70s can directly activate myeloid cells (and, at a lower extent, lymphoid cells) via innate receptors, such as TLR4. All the studies reporting a direct stimulatory activity of HSP70 claimed that this process was independent of contaminating molecules, especially endotoxins (Wang et al. 2010). However, independent studies reported that contaminating endotoxins were responsible for the activation of myeloid cells (Bausinger et al. 2002; Gao and Tsan 2003, 2004). Another study reported that calcium signaling induced by human HSP70 and MtbHSP70 may be caused by contaminating nucleotides (Bendz et al. 2008).
The Immunoregulatory Properties of HSP70
HSP70s are highly conserved molecules which can be released in the extracellular milieu. Consequently, the initiation of HSP70-specific immune responses remains exceptional. Contrary to the vast majority of studies, some authors have reported that HSP70 exhibit regulatory properties (reviewed in (Borges et al. 2012; van Eden et al. 2005). The initial study on a potential regulatory role for HSP70s was the demonstration that MtbHSP70 has an anti-inflammatory role in an in vivo model of autoimmune arthritis model (van Eden et al. 1998). The anti-inflammatory and protective roles of HSP70s and of selected HSP70 peptides have been thereafter reported in different models of severe or chronic inflammation (Vinokurov et al. 2012; Yurinskaya et al. 2009), infection (Kimura et al. 1998) and skin allografts (Borges et al. 2010). Extracellular HSP70s also induce endotoxin tolerance in macrophages (Aneja et al. 2006).
At the cellular level, HSP70 have been also reported to inhibit the maturation of dendritic cells, to induce the differentiation of monocyte-derived dendritic cells into tolerogenic cells (Motta et al. 2007; Stocki and Dickinson 2012) and to potentiate the suppressive activity of myeloid derived suppressive cells (MDSC) (Diao et al. 2015). By inducing suppressive myeloid cells, HSP70s increase the immunosuppressive activity of CD4+ CD25+ FoxP3+ regulatory T cells (Wachstein et al. 2012); regulatory T cells (Treg) have the unique capacity to dampen inflammation and to maintain an immunoregulatory environment (Josefowicz et al. 2012). HSP70s also favor the production of immunosuppressive Th2 cytokines by CD4+ T cells (Tsan and Gao 2004).
Macrophages are involved in numerous processes, such as immune surveillance and wound healing. A binary classification has thus been proposed to define their functional polarization with M1 and M2 cells representing the extremes of a continuum of polarization profiles. M1 cells exhibit antimicrobial and antitumor properties while M2 cells, mainly involved in tissue homeostasis and repair, exhibit immunoregulatory and protumoral properties. In established solid tumors, tumor-associated macrophages (TAM) exhibit a M2 phenotype (Mantovani et al. 2017). As examples, SR-A1 promotes tumor progression in murine models of ovarian and pancreatic cancer (Neyen et al. 2013a, b). HSP70s favor the polarization of macrophages into regulatory M2 cells (Lopes et al. 2014). An intriguing study recently reported that HSP70 regulates the M2-like polarization of tumor-associated macrophages in a SR-A1-dependent manner, favoring in vivo glioma regression (Zhang et al. 2016). However, whether this mechanism can be extended to other HSP70-binding elements, and especially scavenger receptors and C-type lectins, remains unknown.
The immunoregulatory activity of HSP70 was demonstrated to be dependent on the induction of the suppressive cytokine IL-10 by myeloid cells ((Detanico et al. 2004; Kimura et al. 1998; van Eden et al. 2005; Wendling et al. 2000). HSP70-induced IL-10 may then favor the generation of regulatory cells (Treg) as Treg cell depletion completely abolished this effect (Hauet-Broere et al. 2006). The capacity of HSP70 to favor a M2 polarization was also suspected dependent on the induction of IL-10 (Lopes et al. 2016). More recent studies have shown that the capacity of HSP70 to inhibit the production of IL-10 is driven by a down-regulation of the transcription factors C/EBPβ and C/EBPδ (Borges et al. 2013); this inhibition was correlated with a decreased production of pro-inflammatory cytokines and abrogated upon pretreatment of cells with ERK and JAK2/STAT3 inhibitors. These results are in agreement with studies reporting the pivotal role played by STAT3 in the establishment of an immunoregulatory environment (Yu et al. 2007). More intriguingly, Chandarwakar et al reported that the regulatory versus stimulatory activity of HSP was dependent on their concentrations with low doses being efficient to initiate antitumor immune responses and high doses being inefficient or even immunosuppressive (Chandawarkar et al. 1999).
Can SIGLEC4/15 Reconciliate Stimulatory and Regulatory Immune Properties of HSP70?
In 2015, Fong et al reported that the immune properties of extracellular HSP70s are mediated via the receptors Siglec-5 and Siglec-14 (Fong et al. 2015). Siglecs are transmembrane sialic acid-binding immunoglobulin-like lectins mainly expressed on leukocytes (Macauley and Paulson 2014; Schwarz et al. 2015). Siglec-5 and Siglec-14 belong to the rapidly evolving CD33-related Siglecs (CD33rSiglecs) family (Angata 2006). Siglec-5 and Siglec-14 are immune-suppressive and immune-activating paired receptors. This study reported that HSP70s bind Siglec-5 and Siglec-14 in a sialic-acid independent manner and that Hsp70 suppresses inflammation through Siglec-5 while, in contrast, its augments inflammation through Siglec-14. Interestingly, Siglec-5 and Siglec-14 can interact with other HSP70-binding elements, such as TLR and scavenger receptors/C-type lectins which have been defined as HSP70-binding elements. In addition to shed new light on the complexity of the biology of extracellular HSP70, this study provides an elegant molecular demonstration of the dichotomous immune properties of HSP70s and may help clarifying contradictory studies on the immune properties of HSP70s.
HSP70-Based Strategies to Induce Protective Immune Responses
Even though the intrinsic immune properties of HSP70 remain unclear, most authors agree on the fact that HSP70s represent unique vehicles to induce protective antitumoral and antimicrobial CD8+ and CD4+ T cell responses in vivo (Blachere et al. 1997; SenGupta et al. 2004; Udono et al. 1994; Udono and Srivastava 1993), thanks to their capacity to carry exogenous antigens into MHC-I and MHC-II antigen presentation pathways in professional APCs (Castellino et al. 2000; Srivastava 2002). Accordingly, different vaccine strategies have been proposed based on these unique immune properties. A recent review summarized some ongoing antitumoral vaccine clinical trials using HSP (Shevtsov and Multhoff 2016). In this paragraph are only mentioned the different HSP70-based vaccine strategies to induce protective antitumor and antiviral immune responses.
The initial HSP70-based vaccine strategies relied on the peptide-biding capacity of HSP. Vaccines contained HSP70 isolated from tumor (or virus infected) cells (Noessner et al. 2002). In this approach, the antigen specificity is determined by the chaperone-assisted peptides, allowing proposing individual vaccines irrespective of the nature of the vaccine antigens and of the MHC restriction (Suto and Srivastava 1995). HSP70s can be also isolated from the supernatants of apoptotic or stressed tumor cells (Chen et al. 2009; Masse et al. 2004) or from HSP70-transfected tumor cells (Massa et al. 2004). An original approach was the use of HSP70 isolated from dendritic/tumor cell fusion which induce potent antigen-specific antitumor immune responses, superior to the one of HSP70 isolated from tumor cells. (Enomoto et al. 2006). Another peptide-based approach is to reconstitute HSP-peptides complexes with immunodominant tumor antigen peptides (Blachere et al. 1997). Vaccinations with dendritic cells pulsed with tumor-derived HSP70 can also induce protective immune responses (Toomey et al. 2008).
Other strategies are based on the capacity of HSP70 to target dendritic cells in vivo, allowing the antigen to get access to the antigen presentation pathways. In this case, HSP70, coupled to the vaccine antigen, is used as a vaccine vehicle. Vaccine antigens can be chemically coupled to HSP70 (Delneste et al. 2002) or produced as a recombinant fusion molecule (Zhang and Huang 2006). Fusion proteins, consisting in HSP70 coupled to a vaccine antigen, have been validated using several different tumor antigens, such mesothelin, MAGE-1, PSA, carcinoembyonic antigen and Her2/neu (Ge et al. 2009; Yuan et al. 2014; Dong et al. 2013; Jiang et al. 2013; Pakravan et al. 2010; Wu et al. 2005) as well as viral antigens, such as the HPV16 E7 antigen and a dominant epitope of the EBV latent protein 2A (Zong et al. 2009, 2013).
Based on its immunostimulatory properties, other strategies use HSP70s as an adjuvant molecule for vaccines using tumor cell lysates (Wang et al. 2010; Li et al. 2010) or DNA vaccines as a source of antigens (Li et al. 2007; Zhang et al. 2007; Farzanehpour et al. 2013; Garrod et al. 2014) or in classical subunit vaccines (Lewis et al. 2014; Li et al. 2010; Shevtsov et al. 2014) to initiate effective immune responses. Nevertheless, in order to ameliorate the efficacy of the vaccine or to overcome the tumor immunosuppressive environment, several studies associated HSP70 vaccines with an adjuvant. In most cases, combining HSP70 vaccine with adjuvant (Delneste et al. 2002) or CD40L (Gao et al. 2012) induced more potent protective immune responses.
Conclusions
The identification of tumor-associated antigens and the presence of circulating tumor specific cytotoxic T lymphocytes (CTLs) in tumor-bearing patients suggested that initiating a protective antitumor immune response is feasible. A lot of work was thus done to propose antitumor vaccine strategies, such as the use of recombinant virus encoding human tumor antigens, tumor cell-derived exosomes or nucleic acid-based vaccines. Following the identification of the antigen cross-presentation process, numerous studies aimed at identifying carrier proteins that may selectively target and activate immature dendritic cells in vivo. HSP70s have thus emerged in the 1990s as powerful vaccine vehicles to initiate potent and protective antitumoral (and antiviral) CD8+ T cell immune responses. This remarkable property is related to the ability of extracellular HSP70s to interact with innate immune receptors involved in antigen cross-presentation. The initiation of an antigen-specific CD8+ T cells response against a neo-antigen requires that dendritic cells are fully activated. In agreement with their vaccine potentials, the initial studies suggested that HSP70s are intrinsically able to activate APCs. However, the exact nature of PRM involved in the immune properties of HSP70s remains, to date, controversed. Members of the scavenger receptor family appear as the less discussed endocytic receptors. Contrastingly, whether HSP70s are suppressive or stimulatory molecules remain debated. Based on the current view of the capacity of the innate immune system to maintain immune homeostasis in response to modified self, one could hypothesize that HSP70s are not stimulating molecules. Nevertheless, to precisely determine the immune status of HSP70s remains a big challenge that would allow reevaluating their therapeutic use.
Abbreviations
- A2M:
-
alpha2 macroglobulin
- Ac-LDL:
-
acetylated low-density lipoprotein
- ADP:
-
adenosine dipohosphate
- AGE:
-
advanced glycation end product
- AIF:
-
apoptosis inducing factor
- APAf-1:
-
apoptotic peptidase activating factor 1
- APC:
-
antigen-presenting cell
- APOER:
-
apolipoprotein E receptor
- ATP:
-
adenosine triphosphate
- Bax:
-
Bcl-2-associated X protein
- BCR:
-
B cell receptor
- BiP:
-
binding immunoglobulin protein
- CCL:
-
C-C motif ligand
- CCR:
-
C-C chemokine receptor
- CD:
-
cluster of differentiation
- CLEC8A:
-
C-type lectin domain family 8 member A
- CLEVER-1:
-
common lymphatic endothelial and vascular endothelial receptor-1
- CTL:
-
cytotoxic T cell
- DAMP:
-
danger-associated molecular pattern
- DC-SIGN:
-
dendritic cell-specific ICAM-grabbing non-integrin
- EBV:
-
Epstein-Barr virus
- EGF-like:
-
and link domain-containing scavenger receptor-1
- ER:
-
endoplasmic reticulum
- ERK:
-
Extracellular signal-regulated kinases
- FAT:
-
fatty acid translocase
- FEEL-1:
-
fasciclin EGF-like laminin-type
- HBV:
-
hepatitis B virus
- HCV:
-
hepatitis C virus
- Her2/Neu:
-
human epidermal growth factor receptor 2/proto-oncogene Neu
- HLA:
-
human leukocyte antigen
- HMGB1:
-
high–mobility group box 1
- HPV:
-
human papilloma virus
- HSP:
-
heat shock protein
- IFN:
-
interferon
- IL:
-
interleukin
- IRAK:
-
IL-1 receptor-associated kinase
- IRE1α:
-
inositol requiring enzyme 1α
- JAK:
-
Janus kinase
- LBP:
-
LPS-binding protein
- LDL:
-
low-density lipoprotein
- LRP1:
-
low density lipoprotein receptor-related protein 1
- MAGE-1:
-
melanoma-associated antigen 1
- Mart-1:
-
melanoma antigen recognized by T-cells 1
- MD2:
-
myeloid differentiation factor 2
- MDSC:
-
myeloid-derived suppressive cells
- MHC:
-
major histocompatibility complex
- MyD88:
-
Myeloid differentiation primary response 88
- NBD:
-
nucleotide-binding domain
- NF-κB:
-
nuclear factor-kappa B
- NK:
-
natural killer
- Ox-LDL:
-
oxidized low-density lipoprotein
- PAMP:
-
pathogen-associated molecular pattern
- PDZK:
-
PDZ domain-containing protein 1
- PRM:
-
pattern recognition molecule
- PRR:
-
pattern recognition receptor
- PSA:
-
prostate-specific antigen
- PTX3:
-
pentraxin 3
- RAP:
-
receptor-associated protein
- SBD:
-
substrate-binding domain
- SIGLEC:
-
sialic-acid-binding immunoglobulin-like lectins
- SP-D:
-
surfactant protein D
- SREC:
-
scavenger receptor expressed by endothelial cells
- STAT:
-
signal transducers and activators of transcription
- TAB1:
-
TAK1-binding protein 1
- TAK1:
-
TGFβ-activated kinase
- TAM:
-
tumor-associated macrophages
- TCR:
-
T cell receptor
- Th:
-
helper T cell
- TLR:
-
toll-like receptor
- TNF:
-
tumor necrosis factor
- TNFSF:
-
TNF superfamily
- TRAF:
-
TNF receptor-associated factor
- Trp2:
-
tyrosinase-related protein 2
- TSP-1:
-
thrombospondin 1
References
Adachi, H., & Tsujimoto, M. (2002). FEEL-1, a novel scavenger receptor with in vitro bacteria-binding and angiogenesis-modulating activities. The Journal of Biological Chemistry, 277, 34264–34270.
Aneja, R., Odoms, K., Dunsmore, K., Shanley, T. P., & Wong, H. R. (2006). Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. Journal of Immunology, 177, 7184–7192.
Angata, T. (2006). Molecular diversity and evolution of the Siglec family of cell-surface lectins. Molecular Diversity, 10, 555–566.
Arnold-Schild, D., Hanau, D., Spehner, D., et al. (1999). Cutting edge: Receptor-mediated endocytosis of heat shock proteins by professional antigen-presenting cells. Journal of Immunology, 162, 3757–3760.
Asea, A., Kraeft, S. K., Kurt-Jones, E. A., et al. (2000). HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nature Medicine, 6, 435–442.
Asea, A., Rehli, M., Kabingu, E., et al. (2002). Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. The Journal of Biological Chemistry, 277, 15028–15034.
Banchereau, J., Bazan, F., Blanchard, D., et al. (1994). The CD40 antigen and its ligand. Annual Review of Immunology, 12, 881–922.
Banchereau, J., Briere, F., Caux, C., et al. (2000). Immunobiology of dendritic cells. Annual Review of Immunology, 18, 767–811.
Baraldi, P. G., Di Virgilio, F., & Romagnoli, R. (2004). Agonists and antagonists acting at P2X7 receptor. Current Topics in Medicinal Chemistry, 4, 1707–1717.
Basu, S., Binder, R. J., Ramalingam, T., & Srivastava, P. K. (2001). CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity, 14, 303–313.
Batra, L., Verma, S. K., Nagar, D. P., et al. (2014). HSP70 domain II of Mycobacterium tuberculosis modulates immune response and protective potential of F1 and LcrV antigens of Yersinia pestis in a mouse model. PLoS Neglected Tropical Diseases, 8, e3322.
Bausinger, H., Lipsker, D., Ziylan, U., et al. (2002). Endotoxin-free heat-shock protein 70 fails to induce APC activation. European Journal of Immunology, 32, 3708–3713.
Becker, T., Hartl, F. U., & Wieland, F. (2002). CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. The Journal of Cell Biology, 158, 1277–1285.
Beere, H. M., Wolf, B. B., Cain, K., et al. (2000). Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nature Cell Biology, 2, 469–475.
Bendz, H., Marincek, B. C., Momburg, F., et al. (2008). Calcium signaling in dendritic cells by human or mycobacterial Hsp70 is caused by contamination and is not required for Hsp70-mediated enhancement of cross-presentation. The Journal of Biological Chemistry, 283, 26477–26483.
Berwin, B., Hart, J. P., Pizzo, S. V., & Nicchitta, C. V. (2002). Cutting edge: CD91-independent cross-presentation of GRP94(gp96)-associated peptides. Journal of Immunology, 168, 4282–4286.
Binder, R. J. (2009). CD40-independent engagement of mammalian hsp70 by antigen-presenting cells. Journal of Immunology, 182, 6844–6850.
Binder, R. J., & Srivastava, P. K. (2004). Essential role of CD91 in re-presentation of gp96-chaperoned peptides. Proceedings of the National Academy of Sciences of the United States of America, 101, 6128–6133.
Binder, R. J., & Srivastava, P. K. (2005). Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nature Immunology, 6, 593–599.
Binder, R. J., Harris, M. L., Menoret, A., & Srivastava, P. K. (2000). Saturation, competition, and specificity in interaction of heat shock proteins (hsp) gp96, hsp90, and hsp70 with CD11b+ cells. Journal of Immunology, 165, 2582–2587.
Blachere, N. E., Li, Z., Chandawarkar, R. Y., et al. (1997). Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. The Journal of Experimental Medicine, 186, 1315–1322.
Blander, J. M., & Medzhitov, R. (2006). Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature, 440, 808–812.
Borges, T. J., Porto, B. N., Teixeira, C. A., et al. (2010). Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells. PLoS One, 5, e14264.
Borges, T. J., Wieten, L., van Herwijnen, M. J., et al. (2012). The anti-inflammatory mechanisms of Hsp70. Frontiers in Immunology, 3, 95.
Borges, T. J., Lopes, R. L., Pinho, N. G., Machado, F. D., Souza, A. P., & Bonorino, C. (2013). Extracellular Hsp70 inhibits pro-inflammatory cytokine production by IL-10 driven down-regulation of C/EBPbeta and C/EBPdelta. International Journal of Hyperthermia, 29, 455–463.
Bottger, E., Multhoff, G., Kun, J. F., & Esen, M. (2012). Plasmodium falciparum-infected erythrocytes induce granzyme B by NK cells through expression of host-Hsp70. PLoS One, 7, e33774.
Bozzacco, L., Trumpfheller, C., Siegal, F. P., et al. (2007). DEC-205 receptor on dendritic cells mediates presentation of HIV gag protein to CD8+ T cells in a spectrum of human MHC I haplotypes. Proceedings of the National Academy of Sciences of the United States of America, 104, 1289–1294.
Brocchieri, L., Conway de Macario, E., & Macario, A. J. (2008). hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions. BMC Evolutionary Biology, 8, 19.
Bryant, C. E., Gay, N. J., Heymans, S., Sacre, S., Schaefer, L., & Midwood, K. S. (2015). Advances in toll-like receptor biology: Modes of activation by diverse stimuli. Critical Reviews in Biochemistry and Molecular Biology, 50, 359–379.
Campisi, J., & Fleshner, M. (2003). Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. Journal of Applied Physiology (1985), 94, 43–52.
Castelli, C., Ciupitu, A. M., Rini, F., et al. (2001). Human heat shock protein 70 peptide complexes specifically activate antimelanoma T cells. Cancer Research, 61, 222–227.
Castellino, F., Boucher, P. E., Eichelberg, K., et al. (2000). Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. The Journal of Experimental Medicine, 191, 1957–1964.
Cella, M., Sallusto, F., & Lanzavecchia, A. (1997). Origin, maturation and antigen presenting function of dendritic cells. Current Opinion in Immunology, 9, 10–16.
Chandawarkar, R. Y., Wagh, M. S., & Srivastava, P. K. (1999). The dual nature of specific immunological activity of tumor-derived gp96 preparations. The Journal of Experimental Medicine, 189, 1437–1442.
Chen, T., Guo, J., Han, C., Yang, M., & Cao, X. (2009). Heat shock protein 70, released from heat-stressed tumor cells, initiates antitumor immunity by inducing tumor cell chemokine production and activating dendritic cells via TLR4 pathway. Journal of Immunology, 182, 1449–1459.
Clark, P. R., & Menoret, A. (2001). The inducible Hsp70 as a marker of tumor immunogenicity. Cell Stress & Chaperones, 6, 121–125.
Cunin, P., Beauvillain, C., Miot, C., et al. (2016). Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses. Cell Death & Disease, 7, e2215.
Dabaghian, M., Latifi, A. M., Tebianian, M., Dabaghian, F., & Ebrahimi, S. M. (2015). A truncated C-terminal fragment of Mycobacterium tuberculosis HSP70 enhances cell-mediated immune response and longevity of the total IgG to influenza A virus M2e protein in mice. Antiviral Research, 120, 23–31.
Delneste, Y., Magistrelli, G., Gauchat, J., et al. (2002). Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity, 17, 353–362.
Detanico, T., Rodrigues, L., Sabritto, A. C., et al. (2004). Mycobacterial heat shock protein 70 induces interleukin-10 production: Immunomodulation of synovial cell cytokine profile and dendritic cell maturation. Clinical and Experimental Immunology, 135, 336–342.
Diao, J., Yang, X., Song, X., et al. (2015). Exosomal Hsp70 mediates immunosuppressive activity of the myeloid-derived suppressor cells via phosphorylation of Stat3. Medical Oncology, 32, 453.
Dong, L., Zhang, X., Ren, J., et al. (2013). Human prostate stem cell antigen and HSP70 fusion protein vaccine inhibits prostate stem cell antigen-expressing tumor growth in mice. Cancer Biotherapy & Radiopharmaceuticals, 28, 391–397.
Enomoto, Y., Bharti, A., Khaleque, A. A., et al. (2006). Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells. Journal of Immunology, 177, 5946–5955.
Evdonin, A. L., Guzhova, I. V., Margulis, B. A., & Medvedeva, N. D. (2004). Phospholipse c inhibitor, u73122, stimulates release of hsp-70 stress protein from A431 human carcinoma cells. Cancer Cell International, 4, 2.
Facciponte, J. G., Wang, X. Y., & Subjeck, J. R. (2007). Hsp110 and Grp170, members of the Hsp70 superfamily, bind to scavenger receptor-A and scavenger receptor expressed by endothelial cells-I. European Journal of Immunology, 37, 2268–2279.
Fang, H., Wu, Y., Huang, X., et al. (2011). Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. The Journal of Biological Chemistry, 286, 30393–30400.
Farzanehpour, M., Soleimanjahi, H., Hassan, Z. M., Amanzadeh, A., Ghaemi, A., & Fazeli, M. (2013). HSP70 modified response against HPV based tumor. European Review for Medical and Pharmacological Sciences, 17, 228–234.
Fischer, N., Haug, M., Kwok, W. W., et al. (2010). Involvement of CD91 and scavenger receptors in Hsp70-facilitated activation of human antigen-specific CD4+ memory T cells. European Journal of Immunology, 40, 986–997.
Fleshner, M., & Johnson, J. D. (2005). Endogenous extra-cellular heat shock protein 72: Releasing signal(s) and function. International Journal of Hyperthermia, 21, 457–471.
Floto, R. A., MacAry, P. A., Boname, J. M., et al. (2006). Dendritic cell stimulation by mycobacterial Hsp70 is mediated through CCR5. Science, 314, 454–458.
Fong, J. J., Sreedhara, K., Deng, L., et al. (2015). Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 and Siglec-14. The EMBO Journal, 34, 2775–2788.
Gao, B., & Tsan, M. F. (2003). Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor alpha release by murine macrophages. The Journal of Biological Chemistry, 278, 174–179.
Gao, B., & Tsan, M. F. (2004). Induction of cytokines by heat shock proteins and endotoxin in murine macrophages. Biochemical and Biophysical Research Communications, 317, 1149–1154.
Gao, J., Luo, S. M., Peng, M. L., & Deng, T. (2012). Enhanced immunity against hepatoma induced by dendritic cells pulsed with Hsp70-H22 peptide complexes and CD40L. Journal of Cancer Research and Clinical Oncology, 138, 917–926.
Garcia-Vallejo, J. J., Unger, W. W., Kalay, H., & van Kooyk, Y. (2013). Glycan-based DC-SIGN targeting to enhance antigen cross-presentation in anticancer vaccines. Oncoimmunology, 2, e23040.
Garrod, T., Grubor-Bauk, B., Yu, S., Gargett, T., & Gowans, E. J. (2014). Encoded novel forms of HSP70 or a cytolytic protein increase DNA vaccine potency. Human Vaccines & Immunotherapeutics, 10, 2679–2683.
Gastpar, R., Gehrmann, M., Bausero, M. A., et al. (2005). Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Research, 65, 5238–5247.
Ge, W., Hu, P. Z., Huang, Y., et al. (2009). The antitumor immune responses induced by nanoemulsion-encapsulated MAGE1-HSP70/SEA complex protein vaccine following different administration routes. Oncology Reports, 22, 915–920.
Gehrmann, M., Cervello, M., Montalto, G., et al. (2014a). Heat shock protein 70 serum levels differ significantly in patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Frontiers in Immunology, 5, 307.
Gehrmann, M., Specht, H. M., Bayer, C., et al. (2014b). Hsp70 – A biomarker for tumor detection and monitoring of outcome of radiation therapy in patients with squamous cell carcinoma of the head and neck. Radiation Oncology, 9, 131.
Gong, J., Zhu, B., Murshid, A., et al. (2009). T cell activation by heat shock protein 70 vaccine requires TLR signaling and scavenger receptor expressed by endothelial cells-1. Journal of Immunology, 183, 3092–3098.
Gong, J., Zhang, Y., Durfee, J., et al. (2010). A heat shock protein 70-based vaccine with enhanced immunogenicity for clinical use. Journal of Immunology, 184, 488–496.
Gross, C., Koelch, W., DeMaio, A., Arispe, N., & Multhoff, G. (2003a). Cell surface-bound heat shock protein 70 (Hsp70) mediates perforin-independent apoptosis by specific binding and uptake of granzyme B. The Journal of Biological Chemistry, 278, 41173–41181.
Gross, C., Schmidt-Wolf, I. G., Nagaraj, S., et al. (2003b). Heat shock protein 70-reactivity is associated with increased cell surface density of CD94/CD56 on primary natural killer cells. Cell Stress & Chaperones, 8, 348–360.
Gross, C., Holler, E., Stangl, S., et al. (2008). An Hsp70 peptide initiates NK cell killing of leukemic blasts after stem cell transplantation. Leukemia Research, 32, 527–534.
Guo, F., Sigua, C., Bali, P., et al. (2005). Mechanistic role of heat shock protein 70 in Bcr-Abl-mediated resistance to apoptosis in human acute leukemia cells. Blood, 105, 1246–1255.
Hauet-Broere, F., Wieten, L., Guichelaar, T., Berlo, S., van der Zee, R., & Van Eden, W. (2006). Heat shock proteins induce T cell regulation of chronic inflammation. Annals of the Rheumatic Diseases, 65(Suppl 3), iii65–iii68.
Haug, M., Schepp, C. P., Kalbacher, H., Dannecker, G. E., & Holzer, U. (2007). 70-kDa heat shock proteins: Specific interactions with HLA-DR molecules and their peptide fragments. European Journal of Immunology, 37, 1053–1063.
Heath, W. R., & Carbone, F. R. (1999). Cytotoxic T lymphocyte activation by cross-priming. Current Opinion in Immunology, 11, 314–318.
Heath, W. R., & Carbone, F. R. (2001). Cross-presentation in viral immunity and self-tolerance. Nature Reviews. Immunology, 1, 126–134.
Henson, P. M. (2017). Cell removal: Efferocytosis. Annual Review of Cell and Developmental Biology, 33, 127–144.
Herz, J., & Strickland, D. K. (2001). LRP: A multifunctional scavenger and signaling receptor. The Journal of Clinical Investigation, 108, 779–784.
Ishii, T., Udono, H., Yamano, T., et al. (1999). Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. Journal of Immunology, 162, 1303–1309.
Jacquemin, C., Rambert, J., Guillet, S., et al. (2017). HSP70 potentiates interferon-alpha production by plasmacytoid dendritic cells: Relevance for cutaneous lupus and vitiligo pathogenesis. British Journal of Dermatology, 177(5), 1367–1375.
Jaillon, S., Jeannin, P., Hamon, Y., et al. (2009). Endogenous PTX3 translocates at the membrane of late apoptotic human neutrophils and is involved in their engulfment by macrophages. Cell Death and Differentiation, 16, 465–474.
Jeannin, P., Jaillon, S., & Delneste, Y. (2008). Pattern recognition receptors in the immune response against dying cells. Current Opinion in Immunology, 20, 530–537.
Jiang, J., Xie, D., Zhang, W., Xiao, G., & Wen, J. (2013). Fusion of Hsp70 to Mage-a1 enhances the potency of vaccine-specific immune responses. Journal of Translational Medicine, 11, 300.
Josefowicz, S. Z., Lu, L. F., & Rudensky, A. Y. (2012). Regulatory T cells: Mechanisms of differentiation and function. Annual Review of Immunology, 30, 531–564.
Karyampudi, L., & Ghosh, S. K. (2008). Mycobacterial HSP70 as an adjuvant in the design of an idiotype vaccine against a murine lymphoma. Cellular Immunology, 254, 74–80.
Kimura, Y., Yamada, K., Sakai, T., et al. (1998). The regulatory role of heat shock protein 70-reactive CD4+ T cells during rat listeriosis. International Immunology, 10, 117–130.
Kropp, L. E., Garg, M., & Binder, R. J. (2010). Ovalbumin-derived precursor peptides are transferred sequentially from gp96 and calreticulin to MHC class I in the endoplasmic reticulum. Journal of Immunology, 184, 5619–5627.
Krupka, M., Zachova, K., Cahlikova, R., et al. (2015). Endotoxin-minimized HIV-1 p24 fused to murine hsp70 activates dendritic cells, facilitates endocytosis and p24-specific Th1 response in mice. Immunology Letters, 166, 36–44.
Kuppner, M. C., Gastpar, R., Gelwer, S., et al. (2001). The role of heat shock protein (hsp70) in dendritic cell maturation: hsp70 induces the maturation of immature dendritic cells but reduces DC differentiation from monocyte precursors. European Journal of Immunology, 31, 1602–1609.
Lancaster, G. I., & Febbraio, M. A. (2005). Exosome-dependent trafficking of HSP70: A novel secretory pathway for cellular stress proteins. The Journal of Biological Chemistry, 280, 23349–23355.
Lewis, D. J., Wang, Y., Huo, Z., et al. (2014). Effect of vaginal immunization with HIVgp140 and HSP70 on HIV-1 replication and innate and T cell adaptive immunity in women. Journal of Virology, 88, 11648–11657.
Li, H., Ou, X., & Xiong, J. (2007). Modified HPV16 E7/HSP70 DNA vaccine with high safety and enhanced cellular immunity represses murine lung metastatic tumors with downregulated expression of MHC class I molecules. Gynecologic Oncology, 104, 564–571.
Li, H., Yu, Y., Sun, L., et al. (2010). Vaccination with B16 tumor cell lysate plus recombinant Mycobacterium tuberculosis Hsp70 induces antimelanoma effect in mice. Cancer Biotherapy & Radiopharmaceuticals, 25, 185–191.
Li, J., Xing, Y., Zhou, Z., et al. (2016). Microbial HSP70 peptide epitope 407-426 as adjuvant in tumor-derived autophagosome vaccine therapy of mouse lung cancer. Tumour Biology, 37, 15097–15105.
Liu, G., Yao, K., Wang, B., et al. (2009). Immunotherapy of Epstein-Barr virus associated malignancies using mycobacterial HSP70 and LMP2A356-364 epitope fusion protein. Cellular & Molecular Immunology, 6, 423–431.
Liu, G., Yao, K., Wang, B., et al. (2011). Reconstituted complexes of mycobacterial HSP70 and EBV LMP2A-derived peptides elicit peptide-specific cytotoxic T lymphocyte responses and anti-tumor immunity. Vaccine, 29, 7414–7423.
Lopes, R. L., Borges, T. J., Araujo, J. F., et al. (2014). Extracellular mycobacterial DnaK polarizes macrophages to the M2-like phenotype. PLoS One, 9, e113441.
Lopes, R. L., Borges, T. J., Zanin, R. F., & Bonorino, C. (2016). IL-10 is required for polarization of macrophages to M2-like phenotype by mycobacterial DnaK (heat shock protein 70). Cytokine, 85, 123–129.
MacAry, P. A., Javid, B., Floto, R. A., et al. (2004). HSP70 peptide binding mutants separate antigen delivery from dendritic cell stimulation. Immunity, 20, 95–106.
Macauley, M. S., & Paulson, J. C. (2014). Siglecs induce tolerance to cell surface antigens by BIM-dependent deletion of the antigen-reactive B cells. Journal of Immunology, 193, 4312–4321.
MacKenzie, A., Wilson, H. L., Kiss-Toth, E., Dower, S. K., North, R. A., & Surprenant, A. (2001). Rapid secretion of interleukin-1beta by microvesicle shedding. Immunity, 15, 825–835.
Mambula, S. S., & Calderwood, S. K. (2006a). Heat induced release of Hsp70 from prostate carcinoma cells involves both active secretion and passive release from necrotic cells. International Journal of Hyperthermia, 22, 575–585.
Mambula, S. S., & Calderwood, S. K. (2006b). Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. Journal of Immunology, 177, 7849–7857.
Mantovani, A., Marchesi, F., Malesci, A., Laghi, L., & Allavena, P. (2017). Tumour-associated macrophages as treatment targets in oncology. Nature Reviews. Clinical Oncology, 14, 399–416.
Marotta, F., Koike, K., Lorenzetti, A., et al. (2007). Nutraceutical strategy in aging: Targeting heat shock protein and inflammatory profile through understanding interleukin-6 polymorphism. Annals of the New York Academy of Sciences, 1119, 196–202.
Massa, C., Guiducci, C., Arioli, I., Parenza, M., Colombo, M. P., & Melani, C. (2004). Enhanced efficacy of tumor cell vaccines transfected with secretable hsp70. Cancer Research, 64, 1502–1508.
Massa, C., Melani, C., & Colombo, M. P. (2005). Chaperon and adjuvant activity of hsp70: Different natural killer requirement for cross-priming of chaperoned and bystander antigens. Cancer Research, 65, 7942–7949.
Masse, D., Ebstein, F., Bougras, G., Harb, J., Meflah, K., & Gregoire, M. (2004). Increased expression of inducible HSP70 in apoptotic cells is correlated with their efficacy for antitumor vaccine therapy. International Journal of Cancer, 111, 575–583.
Milani, V., Noessner, E., Ghose, S., et al. (2002). Heat shock protein 70: Role in antigen presentation and immune stimulation. International Journal of Hyperthermia, 18, 563–575.
Millar, D. G., Garza, K. M., Odermatt, B., et al. (2003). Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nature Medicine, 9, 1469–1476.
Mizukami, S., Kajiwara, C., Tanaka, M., Kaisho, T., & Udono, H. (2012). Differential MyD88/IRAK4 requirements for cross-priming and tumor rejection induced by heat shock protein 70-model antigen fusion protein. Cancer Science, 103, 851–859.
Moroi, Y., Mayhew, M., Trcka, J., et al. (2000). Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70. Proceedings of the National Academy of Sciences of the United States of America, 97, 3485–3490.
Moser, C., Schmidbauer, C., Gurtler, U., et al. (2002). Inhibition of tumor growth in mice with severe combined immunodeficiency is mediated by heat shock protein 70 (Hsp70)-peptide-activated, CD94 positive natural killer cells. Cell Stress & Chaperones, 7, 365–373.
Motta, A., Schmitz, C., Rodrigues, L., et al. (2007). Mycobacterium tuberculosis heat-shock protein 70 impairs maturation of dendritic cells from bone marrow precursors, induces interleukin-10 production and inhibits T-cell proliferation in vitro. Immunology, 121, 462–472.
Multhoff, G. (2007). Heat shock protein 70 (Hsp70): Membrane location, export and immunological relevance. Methods, 43, 229–237.
Multhoff, G., & Hightower, L. E. (1996). Cell surface expression of heat shock proteins and the immune response. Cell Stress & Chaperones, 1, 167–176.
Multhoff, G., Botzler, C., Wiesnet, M., et al. (1995). A stress-inducible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells. International Journal of Cancer, 61, 272–279.
Mycko, M. P., Cwiklinska, H., Szymanski, J., et al. (2004). Inducible heat shock protein 70 promotes myelin autoantigen presentation by the HLA class II. Journal of Immunology, 172, 202–213.
Narni-Mancinelli, E., Ugolini, S., & Vivier, E. (2013). Tuning the threshold of natural killer cell responses. Current Opinion in Immunology, 25, 53–58.
Neyen, C., Mukhopadhyay, S., Gordon, S., & Hagemann, T. (2013a). An apolipoprotein A-I mimetic targets scavenger receptor A on tumor-associated macrophages: A prospective anticancer treatment? Oncoimmunology, 2, e24461.
Neyen, C., Pluddemann, A., Mukhopadhyay, S., et al. (2013b). Macrophage scavenger receptor a promotes tumor progression in murine models of ovarian and pancreatic cancer. Journal of Immunology, 190, 3798–3805.
Noessner, E. (2006). Thermal stress-related modulation of tumor cell physiology and immune responses. Cancer Immunology, Immunotherapy, 55, 289–291.
Noessner, E., Gastpar, R., Milani, V., et al. (2002). Tumor-derived heat shock protein 70 peptide complexes are cross-presented by human dendritic cells. Journal of Immunology, 169, 5424–5432.
Pakravan, N., Langroudi, L., Hajimoradi, M., & Hassan, Z. M. (2010). Co-administration of GP96 and Her2/neu DNA vaccine in a Her2 breast cancer model. Cell Stress & Chaperones, 15, 977–984.
Paliwal, P. K., Bansal, A., Sagi, S. S., & Sairam, M. (2011). Intraperitoneal immunization of recombinant HSP70 (DnaK) of Salmonella Typhi induces a predominant Th2 response and protective immunity in mice against lethal Salmonella infection. Vaccine, 29, 6532–6539.
Pawaria, S., & Binder, R. J. (2011). CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nature Communications, 2, 521.
Poccia, F., Piselli, P., Vendetti, S., et al. (1996). Heat-shock protein expression on the membrane of T cells undergoing apoptosis. Immunology, 88, 6–12.
Pockley, A. G., Henderson, B., & Multhoff, G. (2014). Extracellular cell stress proteins as biomarkers of human disease. Biochemical Society Transactions, 42, 1744–1751.
Poon, I. K., Lucas, C. D., Rossi, A. G., & Ravichandran, K. S. (2014). Apoptotic cell clearance: Basic biology and therapeutic potential. Nature Reviews. Immunology, 14, 166–180.
Pullen, S. S., Dang, T. T., Crute, J. J., & Kehry, M. R. (1999). CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. The Journal of Biological Chemistry, 274, 14246–14254.
Radons, J. (2016). The human HSP70 family of chaperones: Where do we stand? Cell Stress & Chaperones, 21, 379–404.
Radons, J., & Multhoff, G. (2005). Immunostimulatory functions of membrane-bound and exported heat shock protein 70. Exercise Immunology Review, 11, 17–33.
Ravagnan, L., Gurbuxani, S., Susin, S. A., et al. (2001). Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nature Cell Biology, 3, 839–843.
Redzovic, A., Gulic, T., Laskarin, G., Eminovic, S., Haller, H., & Rukavina, D. (2015). Heat-shock proteins 70 induce pro-inflammatory maturation program in decidual CD1a(+) dendritic cells. American Journal of Reproductive Immunology, 74, 38–53.
Salimu, J., Spary, L. K., Al-Taei, S., et al. (2015). Cross-presentation of the oncofetal tumor antigen 5T4 from irradiated prostate cancer cells – A key role for heat-shock protein 70 and receptor CD91. Cancer Immunology Research, 3, 678–688.
Sawamura, T., Kume, N., Aoyama, T., et al. (1997). An endothelial receptor for oxidized low-density lipoprotein. Nature, 386, 73–77.
Schwarz, F., Pearce, O. M., Wang, X., et al. (2015). Siglec receptors impact mammalian lifespan by modulating oxidative stress. eLife, 4, e06184.
SenGupta, D., Norris, P. J., Suscovich, T. J., et al. (2004). Heat shock protein-mediated cross-presentation of exogenous HIV antigen on HLA class I and class II. Journal of Immunology, 173, 1987–1993.
Shevtsov, M., & Multhoff, G. (2016). Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Frontiers in Immunology, 7, 171.
Shevtsov, M. A., Pozdnyakov, A. V., Mikhrina, A. L., et al. (2014). Effective immunotherapy of rat glioblastoma with prolonged intratumoral delivery of exogenous heat shock protein Hsp70. International Journal of Cancer, 135, 2118–2128.
Singh-Jasuja, H., Toes, R. E., Spee, P., et al. (2000). Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis. The Journal of Experimental Medicine, 191, 1965–1974.
Sondermann, H., Becker, T., Mayhew, M., Wieland, F., & Hartl, F. U. (2000). Characterization of a receptor for heat shock protein 70 on macrophages and monocytes. Biological Chemistry, 381, 1165–1174.
Srivastava, P. (2002). Interaction of heat shock proteins with peptides and antigen presenting cells: Chaperoning of the innate and adaptive immune responses. Annual Review of Immunology, 20, 395–425.
Srivastava, P. K., Menoret, A., Basu, S., Binder, R. J., & McQuade, K. L. (1998). Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world. Immunity, 8, 657–665.
Stocki, P., & Dickinson, A. M. (2012). The immunosuppressive activity of heat shock protein 70. Autoimmune Diseases, 2012, 617213.
Stocki, P., Morris, N. J., Preisinger, C., et al. (2010). Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA). Cell Stress & Chaperones, 15, 729–741.
Stocki, P., Wang, X. N., Morris, N. J., & Dickinson, A. M. (2011). HSP70 natively and specifically associates with an N-terminal dermcidin-derived peptide that contains an HLA-A*03 antigenic epitope. The Journal of Biological Chemistry, 286, 12803–12811.
Suto, R., & Srivastava, P. K. (1995). A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science, 269, 1585–1588.
Suzue, K., & Young, R. A. (1996). Adjuvant-free hsp70 fusion protein system elicits humoral and cellular immune responses to HIV-1 p24. Journal of Immunology, 156, 873–879.
Tamura, Y., Peng, P., Liu, K., Daou, M., & Srivastava, P. K. (1997). Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science, 278, 117–120.
Tamura, Y., Adachi, H., Osuga, J., et al. (2003). FEEL-1 and FEEL-2 are endocytic receptors for advanced glycation end products. The Journal of Biological Chemistry, 278, 12613–12617.
Theriault, J. R., Mambula, S. S., Sawamura, T., Stevenson, M. A., & Calderwood, S. K. (2005). Extracellular HSP70 binding to surface receptors present on antigen presenting cells and endothelial/epithelial cells. FEBS Letters, 579, 1951–1960.
Theriault, J. R., Adachi, H., & Calderwood, S. K. (2006). Role of scavenger receptors in the binding and internalization of heat shock protein 70. Journal of Immunology, 177, 8604–8611.
Tobian, A. A., Canaday, D. H., Boom, W. H., & Harding, C. V. (2004a). Bacterial heat shock proteins promote CD91-dependent class I MHC cross-presentation of chaperoned peptide to CD8+ T cells by cytosolic mechanisms in dendritic cells versus vacuolar mechanisms in macrophages. Journal of Immunology, 172, 5277–5286.
Tobian, A. A., Canaday, D. H., & Harding, C. V. (2004b). Bacterial heat shock proteins enhance class II MHC antigen processing and presentation of chaperoned peptides to CD4+ T cells. Journal of Immunology, 173, 5130–5137.
Todryk, S., Melcher, A. A., Hardwick, N., et al. (1999). Heat shock protein 70 induced during tumor cell killing induces Th1 cytokines and targets immature dendritic cell precursors to enhance antigen uptake. Journal of Immunology, 163, 1398–1408.
Toomey, D., Conroy, H., Jarnicki, A. G., Higgins, S. C., Sutton, C., & Mills, K. H. (2008). Therapeutic vaccination with dendritic cells pulsed with tumor-derived Hsp70 and a COX-2 inhibitor induces protective immunity against B16 melanoma. Vaccine, 26, 3540–3549.
Tsan, M. F., & Gao, B. (2004). Heat shock protein and innate immunity. Cellular & Molecular Immunology, 1, 274–279.
Udono, H., & Srivastava, P. K. (1993). Heat shock protein 70-associated peptides elicit specific cancer immunity. The Journal of Experimental Medicine, 178, 1391–1396.
Udono, H., Levey, D. L., & Srivastava, P. K. (1994). Cellular requirements for tumor-specific immunity elicited by heat shock proteins: Tumor rejection antigen gp96 primes CD8+ T cells in vivo. Proceedings of the National Academy of Sciences of the United States of America, 91, 3077–3081.
Vabulas, R. M., Ahmad-Nejad, P., Ghose, S., Kirschning, C. J., Issels, R. D., & Wagner, H. (2002). HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. The Journal of Biological Chemistry, 277, 15107–15112.
van Eden, W., van der Zee, R., Taams, L. S., Prakken, A. B., van Roon, J., & Wauben, M. H. (1998). Heat-shock protein T-cell epitopes trigger a spreading regulatory control in a diversified arthritogenic T-cell response. Immunological Reviews, 164, 169–174.
van Eden, W., van der Zee, R., & Prakken, B. (2005). Heat-shock proteins induce T-cell regulation of chronic inflammation. Nature Reviews. Immunology, 5, 318–330.
van Eden, W., Spiering, R., Broere, F., & van der Zee, R. (2012). A case of mistaken identity: HSPs are no DAMPs but DAMPERs. Cell Stress & Chaperones, 17, 281–292.
Verma, S. K., Batra, L., & Tuteja, U. (2016). A recombinant trivalent fusion protein F1-LcrV-HSP70(II) augments humoral and cellular immune responses and imparts full protection against Yersinia pestis. Frontiers in Microbiology, 7, 1053.
Vinokurov, M., Ostrov, V., Yurinskaya, M., et al. (2012). Recombinant human Hsp70 protects against lipoteichoic acid-induced inflammation manifestations at the cellular and organismal levels. Cell Stress & Chaperones, 17, 89–101.
Vulpis, E., Cecere, F., Molfetta, R., et al. (2017). Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis. Oncoimmunology, 6, e1279372.
Wachstein, J., Tischer, S., Figueiredo, C., et al. (2012). HSP70 enhances immunosuppressive function of CD4(+)CD25(+)FoxP3(+) T regulatory cells and cytotoxicity in CD4(+)CD25(−) T cells. PLoS One, 7, e51747.
Wan, T., Zhou, X., Chen, G., et al. (2004). Novel heat shock protein Hsp70L1 activates dendritic cells and acts as a Th1 polarizing adjuvant. Blood, 103, 1747–1754.
Wang, Y., Kelly, C. G., Karttunen, J. T., et al. (2001). CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity, 15, 971–983.
Wang, Y., Kelly, C. G., Singh, M., et al. (2002). Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. Journal of Immunology, 169, 2422–2429.
Wang, R., Kovalchin, J. T., Muhlenkamp, P., & Chandawarkar, R. Y. (2006). Exogenous heat shock protein 70 binds macrophage lipid raft microdomain and stimulates phagocytosis, processing, and MHC-II presentation of antigens. Blood, 107, 1636–1642.
Wang, Y., Seidl, T., Whittall, T., Babaahmady, K., & Lehner, T. (2010). Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory. European Journal of Immunology, 40, 1628–1638.
Wang, H., Feng, F., Wang, X. P., et al. (2016). Dendritic cells pulsed with Hsp70 and HBxAg induce specific antitumor immune responses in hepatitis B virus-associated hepatocellular carcinoma. Molecular Medicine Reports, 13, 1077–1082.
Wassenberg, J. J., Dezfulian, C., & Nicchitta, C. V. (1999). Receptor mediated and fluid phase pathways for internalization of the ER Hsp90 chaperone GRP94 in murine macrophages. Journal of Cell Science, 112(Pt 13), 2167–2175.
Wei, Y., Xu, Y., Han, X., et al. (2013). Anti-cancer effects of dioscin on three kinds of human lung cancer cell lines through inducing DNA damage and activating mitochondrial signal pathway. Food and Chemical Toxicology, 59, 118–128.
Wendling, U., Paul, L., van der Zee, R., Prakken, B., Singh, M., & van Eden, W. (2000). A conserved mycobacterial heat shock protein (hsp) 70 sequence prevents adjuvant arthritis upon nasal administration and induces IL-10-producing T cells that cross-react with the mammalian self-hsp70 homologue. Journal of Immunology, 164, 2711–2717.
Wu, Y., Wan, T., Zhou, X., et al. (2005). Hsp70-like protein 1 fusion protein enhances induction of carcinoembryonic antigen-specific CD8+ CTL response by dendritic cell vaccine. Cancer Research, 65, 4947–4954.
Yamada, Y., Doi, T., Hamakubo, T., & Kodama, T. (1998). Scavenger receptor family proteins: Roles for atherosclerosis, host defence and disorders of the central nervous system. Cellular and Molecular Life Sciences, 54, 628–640.
Yang, X., Wang, J., Zhou, Y., Wang, Y., Wang, S., & Zhang, W. (2012). Hsp70 promotes chemoresistance by blocking Bax mitochondrial translocation in ovarian cancer cells. Cancer Letters, 321, 137–143.
Yang, Z., Zhuang, L., Szatmary, P., et al. (2015). Upregulation of heat shock proteins (HSPA12A, HSP90B1, HSPA4, HSPA5 and HSPA6) in tumour tissues is associated with poor outcomes from HBV-related early-stage hepatocellular carcinoma. International Journal of Medical Sciences, 12, 256–263.
Yewdell, J. W., Norbury, C. C., & Bennink, J. R. (1999). Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: Implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Advances in Immunology, 73, 1–77.
Yu, H., Kortylewski, M., & Pardoll, D. (2007). Crosstalk between cancer and immune cells: Role of STAT3 in the tumour microenvironment. Nature Reviews. Immunology, 7, 41–51.
Yu, X., Guo, C., Fisher, P. B., Subjeck, J. R., & Wang, X. Y. (2015). Scavenger receptors: Emerging roles in cancer biology and immunology. Advances in Cancer Research, 128, 309–364.
Yuan, J., Kashiwagi, S., Reeves, P., et al. (2014). A novel mycobacterial Hsp70-containing fusion protein targeting mesothelin augments antitumor immunity and prolongs survival in murine models of ovarian cancer and mesothelioma. Journal of Hematology & Oncology, 7, 15.
Yurinskaya, M. M., Vinokurov, M. G., Zatsepina, O. G., et al. (2009). Exogenous heat shock proteins (HSP70) significantly inhibit endotoxin-induced activation of human neutrophils. Doklady Biological Sciences, 426, 298–301.
Zhang, H., & Huang, W. (2006). Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo. Cell Stress & Chaperones, 11, 216–226.
Zhang, X., Yu, C., Zhao, J., et al. (2007). Vaccination with a DNA vaccine based on human PSCA and HSP70 adjuvant enhances the antigen-specific CD8+ T-cell response and inhibits the PSCA+ tumors growth in mice. The Journal of Gene Medicine, 9, 715–726.
Zhang, H., Zhang, W., Sun, X., et al. (2016). Class A1 scavenger receptor modulates glioma progression by regulating M2-like tumor-associated macrophage polarization. Oncotarget, 7, 50099–50116.
Zong, J., Peng, Q., Wang, Q., Zhang, T., Fan, D., & Xu, X. (2009). Human HSP70 and modified HPV16 E7 fusion DNA vaccine induces enhanced specific CD8+ T cell responses and anti-tumor effects. Oncology Reports, 22, 953–961.
Zong, J., Wang, C., Wang, Q., et al. (2013). HSP70 and modified HPV 16 E7 fusion gene without the addition of a signal peptide gene sequence as a candidate therapeutic tumor vaccine. Oncology Reports, 30, 3020–3026.
Acknowledgements
Studies in our laboratory are supported by institutional grants from Inserm and the University of Angers and by grants from the Ligue contre le Cancer and the Cancéropole Grand Ouest. Vincent Larochette is supported by a grant fellowship from the French Ministry of Research and Higher Education. This manuscript was prepared in the context of the LabEX IGO program supported by the National Research Agency via the investment of the future program (ANR-11-LABEX-0016-01).
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Delneste, Y., Larochette, V., Jeannin, P. (2018). Immune Properties of HSP70. In: Asea, A., Kaur, P. (eds) HSP70 in Human Diseases and Disorders. Heat Shock Proteins, vol 14. Springer, Cham. https://doi.org/10.1007/978-3-319-89551-2_9
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