Skip to main content
SpringerLink
Log in

Immune Properties of HSP70

  • Chapter
  • First Online:
Book cover HSP70 in Human Diseases and Disorders

Part of the book series: Heat Shock Proteins ((HESP,volume 14))

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Angata, T. (2006). Molecular diversity and evolution of the Siglec family of cell-surface lectins. Molecular Diversity, 10, 555–566.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Banchereau, J., Bazan, F., Blanchard, D., et al. (1994). The CD40 antigen and its ligand. Annual Review of Immunology, 12, 881–922.

    Article  CAS  PubMed  Google Scholar 

  • Banchereau, J., Briere, F., Caux, C., et al. (2000). Immunobiology of dendritic cells. Annual Review of Immunology, 18, 767–811.

    Article  CAS  PubMed  Google Scholar 

  • Baraldi, P. G., Di Virgilio, F., & Romagnoli, R. (2004). Agonists and antagonists acting at P2X7 receptor. Current Topics in Medicinal Chemistry, 4, 1707–1717.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Binder, R. J. (2009). CD40-independent engagement of mammalian hsp70 by antigen-presenting cells. Journal of Immunology, 182, 6844–6850.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Blander, J. M., & Medzhitov, R. (2006). Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature, 440, 808–812.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Borges, T. J., Wieten, L., van Herwijnen, M. J., et al. (2012). The anti-inflammatory mechanisms of Hsp70. Frontiers in Immunology, 3, 95.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Cella, M., Sallusto, F., & Lanzavecchia, A. (1997). Origin, maturation and antigen presenting function of dendritic cells. Current Opinion in Immunology, 9, 10–16.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Clark, P. R., & Menoret, A. (2001). The inducible Hsp70 as a marker of tumor immunogenicity. Cell Stress & Chaperones, 6, 121–125.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Delneste, Y., Magistrelli, G., Gauchat, J., et al. (2002). Involvement of LOX-1 in dendritic cell-mediated antigen cross-presentation. Immunity, 17, 353–362.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Heath, W. R., & Carbone, F. R. (1999). Cytotoxic T lymphocyte activation by cross-priming. Current Opinion in Immunology, 11, 314–318.

    Article  CAS  PubMed  Google Scholar 

  • Heath, W. R., & Carbone, F. R. (2001). Cross-presentation in viral immunity and self-tolerance. Nature Reviews. Immunology, 1, 126–134.

    Article  CAS  PubMed  Google Scholar 

  • Henson, P. M. (2017). Cell removal: Efferocytosis. Annual Review of Cell and Developmental Biology, 33, 127–144.

    Article  CAS  PubMed  Google Scholar 

  • Herz, J., & Strickland, D. K. (2001). LRP: A multifunctional scavenger and signaling receptor. The Journal of Clinical Investigation, 108, 779–784.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Jeannin, P., Jaillon, S., & Delneste, Y. (2008). Pattern recognition receptors in the immune response against dying cells. Current Opinion in Immunology, 20, 530–537.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Multhoff, G. (2007). Heat shock protein 70 (Hsp70): Membrane location, export and immunological relevance. Methods, 43, 229–237.

    Article  CAS  PubMed  Google Scholar 

  • Multhoff, G., & Hightower, L. E. (1996). Cell surface expression of heat shock proteins and the immune response. Cell Stress & Chaperones, 1, 167–176.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Narni-Mancinelli, E., Ugolini, S., & Vivier, E. (2013). Tuning the threshold of natural killer cell responses. Current Opinion in Immunology, 25, 53–58.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Noessner, E. (2006). Thermal stress-related modulation of tumor cell physiology and immune responses. Cancer Immunology, Immunotherapy, 55, 289–291.

    Article  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Pawaria, S., & Binder, R. J. (2011). CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nature Communications, 2, 521.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Pockley, A. G., Henderson, B., & Multhoff, G. (2014). Extracellular cell stress proteins as biomarkers of human disease. Biochemical Society Transactions, 42, 1744–1751.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Radons, J. (2016). The human HSP70 family of chaperones: Where do we stand? Cell Stress & Chaperones, 21, 379–404.

    Article  CAS  Google Scholar 

  • Radons, J., & Multhoff, G. (2005). Immunostimulatory functions of membrane-bound and exported heat shock protein 70. Exercise Immunology Review, 11, 17–33.

    PubMed  Google Scholar 

  • Ravagnan, L., Gurbuxani, S., Susin, S. A., et al. (2001). Heat-shock protein 70 antagonizes apoptosis-inducing factor. Nature Cell Biology, 3, 839–843.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Sawamura, T., Kume, N., Aoyama, T., et al. (1997). An endothelial receptor for oxidized low-density lipoprotein. Nature, 386, 73–77.

    Article  CAS  PubMed  Google Scholar 

  • Schwarz, F., Pearce, O. M., Wang, X., et al. (2015). Siglec receptors impact mammalian lifespan by modulating oxidative stress. eLife, 4, e06184.

    Article  PubMed Central  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • Shevtsov, M., & Multhoff, G. (2016). Heat shock protein-peptide and HSP-based immunotherapies for the treatment of cancer. Frontiers in Immunology, 7, 171.

    PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • Stocki, P., & Dickinson, A. M. (2012). The immunosuppressive activity of heat shock protein 70. Autoimmune Diseases, 2012, 617213.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • Suto, R., & Srivastava, P. K. (1995). A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science, 269, 1585–1588.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Tsan, M. F., & Gao, B. (2004). Heat shock protein and innate immunity. Cellular & Molecular Immunology, 1, 274–279.

    CAS  Google Scholar 

  • Udono, H., & Srivastava, P. K. (1993). Heat shock protein 70-associated peptides elicit specific cancer immunity. The Journal of Experimental Medicine, 178, 1391–1396.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    PubMed Central  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Laboratory of Immunology and Allergology, University Hospital of Angers, Angers, France

    Yves Delneste & Pascale Jeannin

  2. CRCINA, INSERM, Université de Nantes, Université d’Angers, Angers, France

    Yves Delneste, Vincent Larochette & Pascale Jeannin

  3. LabEx ImmunoGraftOnco, Angers, France

    Yves Delneste, Vincent Larochette & Pascale Jeannin

Authors
  1. Yves Delneste
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vincent Larochette
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pascale Jeannin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yves Delneste .

Editor information

Editors and Affiliations

  1. Department of Medicine and Precision Therapeutics Proteogenomics Diagnostic Center, Eleanor N. Dana Cancer Center, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Punit Kaur

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

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

Download citation

Publish with us

Policies and ethics

Search

Navigation