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Diverse Roles of Heat Shock Proteins in Immune Activation and Tolerance: A Comprehensive Review of Mechanisms and Therapeutic Relevance

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Heat Shock Proteins in Signaling Pathways

Part of the book series: Heat Shock Proteins ((HESP,volume 17))

Abstract

Heat shock proteins (HSP) are a broad set of proteins that are induced by a variety of cellular stresses. These proteins predominantly act as chaperones of other proteins in the cell. Since inflammation and infection are a source of physiologic cellular stress, it is unsurprising that the heat shock protein response and the immune response are closely linked. In this chapter, we explore ways in which HSP participate in diverse immune activities, as well as the therapeutic relevance of HSP-immune crosstalk. Firstly, HSP have been found to positively influence the process of immune activation by stimulating innate immune cells and aiding in antigen processing and presentation. Numerous vaccine strategies have been devised based on the finding that HSP can assist in entry of tumor antigens into antigen processing and presentation pathways. These vaccines, which largely consist of HSP-peptide-complexes, have produced striking therapeutic effects in animal tumor models and early clinical studies. In a seeming paradox, HSP have been shown to support immune tolerance and protect against various forms of autoimmunity in mouse models, possibly through the production of IL-10 by regulatory T-cells. These findings have similarly led to efforts to develop HSP-based therapeutic strategies to reduce inflammation associated with arthritis and other inflammatory conditions. We discuss these concepts in detail, and attempt to shed light on why and how HSP influence the immune system to shift towards activation or tolerance.

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Abbreviations

AA:

adjuvant-induced arthritis

AHR:

aryl hydrocarbon receptor

APC:

antigen-presenting cell

APL:

altered peptide ligand

CTLA-4:

cytotoxic T-lymphocyte-associated protein 4

DC:

dendritic cell

HPV16:

human papilloma virus 16

HSF1:

heat shock factor 1

MHC:

major histocompatibility complex

NK:

natural killer

OVA:

ovalbumin

PD-1:

programmed death 1

RA:

rheumatoid arthritis

TCDD:

2,3,7,8-tetrachlorodibenzo-p-dioxin

TLR:

toll-like receptor

Treg:

regulatory T-cell

References

  • Ampie L, Choy W, Lamano J, Fakurnejad S, Bloch O, Parsa A (2015) Heat shock protein vaccines against glioblastoma: from bench to bedside. J Neuro-Oncol 123:441–448

    Article  CAS  Google Scholar 

  • Anderton SM, van der Zee R, Prakken B, Noordzij A, van Eden W (1995) Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 181:943–952

    Article  CAS  PubMed  Google Scholar 

  • Asea A, Rehli M, Kabingu E, Boch JA, Bare O, Auron PE, Stevenson MA, Calderwood SK (2002) Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem 277:15028–15034

    Article  CAS  PubMed  Google Scholar 

  • Atarashi K, Nishimura J, Shima T, Umesaki Y, Yamamoto M, Onoue M, Yagita H, Ishii N, Evans R, Honda K, Takeda K (2008) ATP drives lamina propria T(H)17 cell differentiation. Nature 455:808–812

    Article  CAS  PubMed  Google Scholar 

  • Barberá A, Lorenzo N, van Kooten P, van Roon J, de Jager W, Prada D, Gómez J, Paón G, van Eden W, Broere F, Del Carmen Domínguez M (2016) APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients. Cell Stress Chaperones 21:735–744

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK (2000) Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-Kappa B pathway. Int Immunol 12:1539–1546

    Article  CAS  PubMed  Google Scholar 

  • Basu S, Binder RJ, Ramalingam T, Srivastava PK (2001) CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14:303–313

    Article  CAS  PubMed  Google Scholar 

  • Belli F, Testori A, Rivoltini L, Maio M, Andreola G, Sertoli MR, Gallino G, Piris A, Cattelan A, Lazzari I, Carrabba M, Scita G, Santantonio C, Pilla L, Tragni G, Lombardo C, Arienti F, Marchianò A, Queirolo P, Bertolini F, Cova A, Lamaj E, Ascani L, Camerini R, Corsi M, Cascinelli N, Lewis JJ, Srivastava P, Parmiani G (2002) Vaccination of metastatic melanoma patients with autologous tumor-derived heat shock protein gp96-peptide complexes: clinical and immunologic findings. J Clin Oncol 20:4169–4180

    Article  CAS  PubMed  Google Scholar 

  • Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, Pahau H, Lee BT, Ng J, Brunck MEG, Hyde C, Trouw LA, Dudek NL, Purcell AW, O’Sullivan BJ, Connolly JE, Paul SK, Lê Cao K, Thomas R (2015) Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci Transl Med 7:290ra87

    Article  PubMed  CAS  Google Scholar 

  • Benson JM, Shepherd DM (2011) Aryl hydrocarbon receptor activation by TCDD reduces inflammation associated with Crohn’s disease. Toxicol Sci Off J Soc Toxicol 120:68–78

    Article  CAS  Google Scholar 

  • Blachere NE, Li Z, Chandawarkar RY, Suto R, Jaikaria NS, Basu S, Udono H, Srivastava PK (1997) Heat shock protein-peptide complexes, reconstituted, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J Exp Med 186:1315–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonorino C, Nardi NB, Zhang X, Wysocki LJ (1998) Characteristics of the strong antibody response to mycobacterial Hsp70: a primary, T cell-dependent IgG response with no evidence of natural priming or γδ T cell involvement. J Immunol (Baltimore, Md.: 1950) 161:5210–5216

    CAS  Google Scholar 

  • Borges TJ, Porto BN, Teixeira CA, Rodrigues M, Machado FD, Ornaghi AP, de Souza APD, Maito F, Pavanelli WR, Silva JS, Bonorino C (2010) Prolonged survival of allografts induced by mycobacterial Hsp70 is dependent on CD4+CD25+ regulatory T cells. PLoS One 5:e14264

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Borges TJ, Wieten L, van Herwijnen MJ, Broere F, van der Zee R, Bonorino C, van Eden W (2012) The anti-inflammatory mechanisms of Hsp70. Front Immunol 3:95

    Article  PubMed  PubMed Central  Google Scholar 

  • Bosch FX, Manos MM, Munoz N, Sherman M, Jansen AM, Peto J, Schiffman MH, Moreno V, Kurman R, Shan KV (1995) Prevalence of human papillomavirus in cervical cancer: a worldwide perspective. J Natl Cancer Inst 87:796–802

    Article  CAS  PubMed  Google Scholar 

  • Breuninger S, Erl J, Knape C, Gunther S, Regel I, Rodel F, Gaipl US, Thorsteinsdottir J, Giannitrapani L, Dickinson AM, Multhoff G (2014) Quantitative analysis of liposomal heat shock protein 70 (Hsp70) in the blood of tumor patients (serum and plasma) using a novel lipHsp70 ELISA. J Clin Cell Immunol 5:264

    Article  Google Scholar 

  • Broquet AH, Thomas G, Masliah JÃ, Trugnan G, Bachelet M (2003) Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J Biol Chem 278:21601–21606

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Barbi J, Shurui B, Yang H-Y, Li Z, Gao Y, Jinasena D, Juan F, Lin F, Chen C, Zhang J, Yu N, Li X, Shan Z, Nie J, Gao Z, Tian H, Li Y, Yao Z, Zheng Y, Park BV, Pan Z, Dang E, Li Z, Wang H, Luo W, Li L, Semenza GL, Zheng S-G, Loser K, Tsun A, Greene MI, Pardoll DM, Pan F, Li B (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39:272–285

    Article  CAS  PubMed  Google Scholar 

  • Chu NR, Wu HB, Wu T, Boux LJ, Siegel MI, Mizzen LA (2000a) Immunotherapy of a human papillomavirus (HPV) type 16 E7-expressing tumour by administration of fusion protein comprising Mycobacterium bovis bacille Calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol 121:216–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chu NR, Wu HB, Wu T-C, Boux LJ, Mizzen LA, Siegel MI (2000b) Immunotherapy of a human papillomavirus type 16 E7-expressing tumor by administration of fusion protein comprised of Mycobacterium bovis BCG Hsp65 and HPV16 E7. Cell Stress Chaperones 5:401–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180:5771–5777

    Article  CAS  PubMed  Google Scholar 

  • Craig EA (1985) The stress response: changes in eukaryotic gene expression in response to environmental stress. Science (New York, NY) 230:800

    Article  CAS  Google Scholar 

  • Cresswell P, Bangia N, Dick T, Diedrich G (1999) The nature of the MHC class I peptide loading complex. Immunol Rev 172:21–28

    Article  CAS  PubMed  Google Scholar 

  • de Wolf C, van der Zee R, den Braber I, Glant T, Maillère B, Favry E, van Lummel M, Koning F, Hoek A, Ludwig I, van Eden W, Broere F (2016) An arthritis-suppressive and Treg cell-inducing CD4+ T cell epitope is functional in the context of HLA-restricted T cell responses. Arthritis Rheumatol 68:639–647

    Article  PubMed  CAS  Google Scholar 

  • DeNagel DC, Pierce SK (1992) A case for chaperones in antigen processing. Immunol Today 13:86–89

    Article  CAS  PubMed  Google Scholar 

  • Detanico T, Rodrigues L, Sabritto AC, Keisermann M, Bauer ME, Zwickey H, Bonorino C (2004) Mycobacterial heat shock protein 70 induces interleukin-10 production: immunomodulation of synovial cell cytokine profile and dendritic cell maturation. Clin Exp Immunol 135:336–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A, Maliszewski C, Akira S, Pulendran B (2004) A toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 172:4733–4743

    Article  CAS  PubMed  Google Scholar 

  • Doody ADH, Kovalchin JT, Mihalyo MA, Hagymasi AT, Drake CG, Adler AJ (2004) Glycoprotein 96 can chaperone both MHC class I- and class II-restricted epitopes for in vivo presentation, but selectively primes CD8+ T cell effector function. J Immunol 172:6087

    Article  CAS  PubMed  Google Scholar 

  • Dressel R (2017) Collaboration of heat shock protein 70 and stress-induced NKG2D ligands in the activation of NK cells against tumors. Curr Immunol Rev 13:56–63

    Article  CAS  Google Scholar 

  • Esterházy D, Loschko J, London M, Jove V, Oliveira TY, Mucida D (2016) Classical dendritic cells are required for dietary antigen-mediated induction of peripheral T(reg) cells and tolerance. Nat Immunol 17:545

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Eton O, Ross MI, East MJ, Mansfield PF, Papadopoulos N, Ellerhorst JA, Bedikian AY, Lee JE (2010) Autologous tumor-derived heat-shock protein peptide complex-96 (HSPPC-96) in patients with metastatic melanoma. J Transl Med 8:9

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Feinstein DL, Galea E, Aquino DA, Li GC, Xu H, Reis DJ (1996) Heat shock protein 70 suppresses astroglial-inducible nitric-oxide synthase expression by decreasing NFkappaB activation. J Biol Chem 271:17724

    Article  CAS  PubMed  Google Scholar 

  • Ferat-Osorio E, Sánchez-Anaya A, Gutiérrez-Mendoza M, Boscó-Gárate I, Wong-Baeza I, Pastelin-Palacios R, Pedraza-Alva G, Bonifaz LC, Cortés-Reynosa P, Pérez-Salazar E, Arriaga-Pizano L, López-Macías C, Rosenstein Y, Isibasi A (2014) Heat shock protein 70 down-regulates the production of toll-like receptor-induced pro-inflammatory cytokines by a heat shock factor-1/constitutive heat shock element-binding factor-dependent mechanism. J Inflamm 11:19

    Article  CAS  Google Scholar 

  • Frankel T, Lanfranca MP, Zou W (2017) The role of tumor microenvironment in cancer immunotherapy. Adv Exp Med Biol 1036:51–64

    Article  CAS  PubMed  Google Scholar 

  • Fuller KJ, Issels RD, Slosman DO, Guillet J, Soussi T, Polla BS (1994) Cancer and the heat shock response. Eur J Cancer 30:1884–1891

    Article  Google Scholar 

  • Gao B, Tsan M (2004) Induction of cytokines by heat shock proteins and endotoxin in murine macrophages. Biochem Biophys Res Commun 317:1149–1154

    Article  CAS  PubMed  Google Scholar 

  • Gastpar R, Gehrmann M, Bausero MA, Asea A, Gross C, Schroeder JA, Multhoff G (2005) Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res 65:5238–5247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hartl FU, Bracher A, Hayer-Hartl M (2011) Molecular chaperones in protein folding and proteostasis. Nature 475:324–332

    Article  CAS  PubMed  Google Scholar 

  • Hendrick JP, Hartl FU (1995) The role of molecular chaperones in protein folding. FASEB J Off Publ Fed Am Soc Exp Biol 9:1559

    CAS  Google Scholar 

  • Hightower LE, Guidon JPT (1989) Selective release from cultured mammalian cells of heat-shock (stress) proteins that resemble glia-axon transfer proteins. J Cell Physiol 138:257–266

    Article  CAS  PubMed  Google Scholar 

  • Hoeger PH, Tepper MA, Faith A, Higgins JA, Lamb JR, Geha RS (1994) Immunosuppressant deoxyspergualin inhibits antigen processing in monocytes. J Immunol 153:3908–3916

    CAS  PubMed  Google Scholar 

  • Holt SE, Aisner DL, Baur J, Tesmer VM, Dy M, Ouellette M, Trager JB, Morin GB, Toft DO, Shay JW, Wright WE, White MA (1999) Functional requirement of p23 and Hsp90 in telomerase complexes. Genes Dev 13:817–826

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y, Takeda K, Akira S (1999) Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749

    CAS  PubMed  Google Scholar 

  • Hua Y, Yang Y, Sun S, Iwanowycz S, Westwater C, Reizis B, Li Z, Liu B (2017) Gut homeostasis and regulatory T cell induction depend on molecular chaperone gp96 in CD11c^sup +^ cells. Sci Rep (Nature Publisher Group) 7:1

    Google Scholar 

  • Isaacs JS, Jung Y, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 α-degradative pathway. J Biol Chem 277:29936

    Article  CAS  PubMed  Google Scholar 

  • Ishii T, Udono H, Yamano T, Ohta H, Uenaka A, Ono T, Hizuta A, Tanaka N, Srivastava PK, Nakayama E (1999) Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96. J Immunol (Baltimore, Md.: 1950) 162:1303–1309

    CAS  Google Scholar 

  • Janetzki S, Palla D, Rosenhauer V, Lochs H, Lewis JJ, Srivastava PK (2000) Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: a pilot study. Int J Cancer 88:232–238

    Article  CAS  PubMed  Google Scholar 

  • Kaiser F, Cook D, Papoutsopoulou S, Rajsbaum R, Wu X, Yang H, Grant S, Ricciardi-Castagnoli P, Tsichlis PN, Ley SC, O’Garra A (2009) TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells. J Exp Med 206:1863–1871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kaufmann SH, Vath U, Thole JE, Van Embden JD, Emmrich F (1987) Enumeration of T cells reactive with Mycobacterium tuberculosis organisms and specific for the recombinant mycobacterial 64-kDa protein. Eur J Immunol 17:351–357

    Article  CAS  PubMed  Google Scholar 

  • Kerkvliet NI, Steppan LB, Vorachek W, Oda S, Farrer D, Wong CP, Pham D, Mourich DV (2009) Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy 1:539–547

    CAS  PubMed  Google Scholar 

  • Kinner-bibeau LB, Sedlacek AL, Messmer MN, Watkins SC, Binder RJ (2017) HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells. Nat Commun 8:15648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koffeman EC, Genovese M, Amox D, Keogh E, Santana E, Matteson EL, Kavanaugh A, Molitor JA, Schiff MH, Posever JO, Bathon JM, Kivitz AJ, Samodal R, Belardi F, Dennehey C, van den Broek T, van Wijk F, Zhang X, Zieseniss P, Le T, Prakken BA, Cutter GC, Albani S (2009) Epitope-specific immunotherapy of rheumatoid arthritis: clinical responsiveness occurs with immune deviation and relies on the expression of a cluster of molecules associated with T cell tolerance in a double-blind, placebo-controlled, pilot phase II trial. Arthritis Rheum 60:3207–3216

    Article  CAS  PubMed  Google Scholar 

  • Kol A, Bourcier T, Lichtman AH, Libby P (1999) Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages. J Clin Invest 103:571–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA (2000) Cutting edge: heat shock protein (HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60 activation of mononuclear cells. J Immunol (Baltimore, Md. : 1950) 164:13

    Article  CAS  Google Scholar 

  • Kovalchin JT, Murthy AS, Horattas MC, Guyton DP, Chandawarkar RY (2001) Determinants of efficacy of immunotherapy with tumor-derived heat shock protein gp96. Cancer Immun 1:7

    CAS  PubMed  Google Scholar 

  • Lewis M, Helmsing PJ, Ashburner M (1975) Parallel changes in puffing activity and patterns of protein synthesis in salivary glands of Drosophila. Proc Natl Acad Sci U S A 72:3604–3608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Z, Srivastava PK (1993) Tumor rejection antigen gp96/grp94 is an ATPase: implications for protein folding and antigen presentation. EMBO J 12:3143–3151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lianos GD, Alexiou GA, Mangano A, Mangano A, Rausei S, Boni L, Dionigi G, Roukos DH (2015) The role of heat shock proteins in cancer. Cancer Lett 360:114–118

    Article  CAS  PubMed  Google Scholar 

  • Lindquist S, Craig EA (1988) The heat-shock proteins. Annu Rev Genet 22:631–677

    Article  CAS  PubMed  Google Scholar 

  • Liu K, Nussenzweig MC (2010) Origin and development of dendritic cells. Immunol Rev 234:45–54

    Article  CAS  PubMed  Google Scholar 

  • Mambula SS, Calderwood SK (2006) Heat shock protein 70 is secreted from tumor cells by a nonclassical pathway involving lysosomal endosomes. J Immunol 177:7849–7857

    Article  CAS  PubMed  Google Scholar 

  • Mbofung RM, McKenzie JA, Malu S, Zhang M, Peng W, Liu C, Kuiatse I, Tieu T, Williams L, Devi S, Ashkin E, Xu C, Huang L, Zhang M, Talukder AH, Tripathi SC, Khong H, Satani N, Muller FL, Roszik J, Heffernan T, Allison JP, Lizee G, Hanash SM, Proia D, Amaria R, Eric Davis R, Hwu P (2017) HSP90 inhibition enhances cancer immunotherapy by upregulating interferon response genes. Nat Commun 8:1

    Article  CAS  Google Scholar 

  • Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190–3198

    Article  CAS  PubMed  Google Scholar 

  • Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M (2004) A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64:4707–4710

    Article  CAS  PubMed  Google Scholar 

  • Mosser DD, Morimoto RI (2004) Molecular chaperones and the stress of oncogenesis. Oncogene 23:2907–2918

    Article  CAS  PubMed  Google Scholar 

  • Mosser DD, Caron AW, Bourget L, Meriin AB, Sherman MY, Morimoto RI, Massie B (2000) The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol 20:7146–7159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Motta A, Schmitz C, Rodrigues L, Ribeiro F, Teixeira C, Detanico T, Bonan C, Zwickey H, Bonorino C (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  CAS  PubMed  PubMed Central  Google Scholar 

  • Moudgil KD, Chang TT, Eradat H, Chen AM, Gupta RS, Brahn E, Sercarz EE (1997) Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J Exp Med 185:1307–1316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moudgil KD, Kim E, Yun OJ, Chi HH, Brahn E, Sercarz EE (2001) Environmental modulation of autoimmune arthritis involves the spontaneous microbial induction of T cell responses to regulatory determinants within heat shock protein 65. J Immunol 166:4237–4243

    Article  CAS  PubMed  Google Scholar 

  • Multhoff G, Botzler C, Jennen L, Schmidt J, Ellwart J, Issels R (1997) Heat shock protein 72 on tumor cells: a recognition structure for natural killer cells. J Immunol 158:4341–4350

    CAS  PubMed  Google Scholar 

  • Multhoff G, Mizzen L, Winchester CC, Milner CM, Wenk S, Eissner G, Kampinga HH, Laumbacher B, Johnson J (1999) Heat shock protein 70 (Hsp70) stimulates proliferation and cytolytic activity of natural killer cells. Exp Hematol 27:1627–1636

    Article  CAS  PubMed  Google Scholar 

  • Munster PN, Marchion DC, Basso AD, Rosen N (2002) Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3′-kinase-AKT-dependent pathway. Cancer Res 62:3132–3137

    CAS  PubMed  Google Scholar 

  • Murray IA, Patterson AD, Perdew GH (2014) Aryl hydrocarbon receptor ligands in cancer: friend and foe. Nat Rev Cancer 14:801–814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murshid A, Gong J, Calderwood SK (2014) Hsp90-peptide complexes stimulate antigen presentation through the class II pathway after binding scavenger receptor SREC-I. Immunobiology 219:924–931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nylandsted J, Rohde M, Brand K, Bastholm L, Elling F, Jaattela M (2000) Selective depletion of heat shock protein 70 (Hsp70) activates a tumor-specific death program that is independent of caspases and bypasses Bcl-2. Proc Natl Acad Sci U S A 97:7871–7876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Garra A, Saraiva M (2010) The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181

    Article  PubMed  CAS  Google Scholar 

  • Ohashi K, Burkart V, Flohe S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164:558

    Article  CAS  PubMed  Google Scholar 

  • Olsen AO, Gjoen K, Sauer T, Orstavik I, Naess O, Kierulf K, Sponland G, Magnus P (1995) Human papillomavirus and cervical intraepithelial neoplasia grade II-III: a population-based case-control study. Int J Cancer 61:312–315

    Article  CAS  PubMed  Google Scholar 

  • Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12:252–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pawaria S, Binder RJ (2011) CD91-dependent programming of T-helper cell responses following heat shock protein immunization. Nat Commun 2:521

    Article  PubMed  CAS  Google Scholar 

  • Pilla L, Squarcina P, Coppa J, Mazzaferro V, Huber V, Pende D, Maccalli C, Sovena G, Mariani L, Castelli C, Parmiani G, Rivoltini L (2005) Natural killer and NK-like T-cell activation in colorectal carcinoma patients treated with autologous tumor-derived heat shock protein 96. Cancer Res 65:3942–3949

    Article  CAS  PubMed  Google Scholar 

  • Pockley AG (2003) Heat shock proteins as regulators of the immune response. Lancet (Lond UK) 362:469–476

    Article  CAS  Google Scholar 

  • Prakken BJ, Samodal R, Le TD, Giannoni F, Yung GP, Scavulli J, Amox D, Roord S, de Kleer I, Bonnin D, Lanza P, Berry C, Massa M, Billetta R, Albani S, Carson DA (2004) Epitope-specific immunotherapy induces immune deviation of proinflammatory T cells in rheumatoid arthritis. Proc Natl Acad Sci U S A 101:4228–4233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pratt WB (1998) The hsp90-based chaperone system: involvement in signal transduction from a variety of hormone and growth factor receptors. Proc Soc Exp Biol Med Soc Exp Biol Med (New York NY) 217:420–434

    Article  CAS  Google Scholar 

  • Quintana FJ (2013) The aryl hydrocarbon receptor: a molecular pathway for the environmental control of the immune response. Immunology 138:183–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quintana FJ, Carmi P, Mor F, Cohen IR (2004) Inhibition of adjuvant-induced arthritis by DNA vaccination with the 70-kd or the 90-kd human heat-shock protein: immune cross-regulation with the 60-kd heat-shock protein. Arthritis Rheum 50:3712–3720

    Article  CAS  PubMed  Google Scholar 

  • Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71

    Article  CAS  PubMed  Google Scholar 

  • Quintana FJ, Murugaiyan G, Farez MF, Mitsdoerffer M, Tukpah A-M, Burns EJ, Weiner HL, Wekerle H (2010) An endogenous aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 107:20768–20773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rippmann F, Taylor WR, Rothbard JB, Green NM (1991) A hypothetical model for the peptide binding domain of hsp70 based on the peptide binding domain of HLA. EMBO J 10:1053–1059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ritossa F (1962) A new puffing pattern induced by temperature shock and DNP in drosophila. Experientia 18:571–573

    Article  CAS  Google Scholar 

  • Round JL, Mazmanian SK, Flavell RA (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci U S A 107:12204–12209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, Benoist C, Rudensky AY (2010) Stability of the regulatory T cell lineage in vivo. Science 329:1667–1671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rutella S, Danese S, Leone G (2006) Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108:1435–1440

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  CAS  PubMed  Google Scholar 

  • Sato K, Torimoto Y, Tamura Y, Shindo M, Shinzaki H, Hirai K, Kohgo Y (2001) Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice. Blood 98:1852–1857

    Article  CAS  PubMed  Google Scholar 

  • Schett G, Redlich K, Xu Q, Bizan P, Gröger M, Tohidast-Akrad M, Kiener H, Smolen J, Steiner G (1998) Enhanced expression of heat shock protein 70 (hsp70) and heat shock factor 1 (HSF1) activation in rheumatoid arthritis synovial tissue. Differential regulation of hsp70 expression and hsf1 activation in synovial fibroblasts by proinflammatory cytokines, shear stress, and antiinflammatory drugs. J Clin Invest 102:302–311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schultz DR, Arnold PI (1993) Heat shock (stress) proteins and autoimmunity in rheumatic diseases. Semin Arthritis Rheum 22:357–374

    Article  CAS  PubMed  Google Scholar 

  • Srivastava P (2002) Roles of heat-shock proteins in innate and adaptive immunity. Nat Rev Immunol 2:185–194

    Article  CAS  PubMed  Google Scholar 

  • Srivastava PK, DeLeo AB, Old LJ (1986) Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc Natl Acad Sci U S A 83:3407–3411

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Srivastava PK, Udono H, Blachere NE, Li Z (1994) Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39:93–98

    Article  CAS  PubMed  Google Scholar 

  • Srivastava PK, Menoret A, Basu S, Binder RJ, McQuade KL (1998) Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity 8:657–665

    Article  CAS  PubMed  Google Scholar 

  • Stangl S, Tontcheva N, Sievert W, Shevtsov M, Niu M, Schmid TE, Pigorsch S, Combs SE, Haller B, Balermpas P, Rodel F, Rodel C, Fokas E, Krause M, Linge A, Lohaus F, Baumann M, Tinhofer I, Budach V, Stuschke M, Grosu AL, Abdollahi A, Debus J, Belka C, Maihofer C, Monnich D, Zips D, Multhoff G (2017) Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Int J Cancer 142:1911–1925

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Steel R, Doherty JP, Buzzard K, Clemons N, Hawkins CJ, Anderson RL (2004) Hsp72 inhibits apoptosis upstream of the mitochondria and not through interactions with Apaf-1. J Biol Chem 279:51490–51499

    Article  CAS  PubMed  Google Scholar 

  • Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711

    Article  CAS  PubMed  Google Scholar 

  • Stocki P, Wang XN, Dickinson AM (2012) Inducible heat shock protein 70 reduces T cell responses and stimulatory capacity of monocyte-derived dendritic cells. J Biol Chem 287:12387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzue K, Zhou X, Eisen HN, Young RA (1997) Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway. Proc Natl Acad Sci U S A 94:13146–13151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takayama S, Reed JC, Homma S (2003) Heat-shock proteins as regulators of apoptosis. Oncogene 22:9041–9047

    Article  CAS  PubMed  Google Scholar 

  • Tamura Y, Peng P, Liu K, Daou M, Srivastava PK (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278:117–120

    Article  CAS  PubMed  Google Scholar 

  • Theriault JR, Adachi H, Calderwood SK (2006) Role of scavenger receptors in the binding and internalization of heat shock protein 70. J Immunol 177:8604–8611

    Article  CAS  PubMed  Google Scholar 

  • Thomson AW, Morelli AE (2007) Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7:610–621

    Article  PubMed  CAS  Google Scholar 

  • Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Stephen Hodi F (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol Off J Am Soc Clin Oncol 32:1020–1030

    Article  CAS  Google Scholar 

  • Udono H, Srivastava PK (1993) Heat shock protein 70-associated peptides elicit specific cancer immunity. J Exp Med 178:1391–1396

    Article  CAS  PubMed  Google Scholar 

  • Udono H, Levey DL, Srivastava PK (1994) Cellular requirements for tumor-specific immunity elicited by heat shock proteins: tumor rejection antigen gp96 primes CD8+T cells in vivo. Proc Natl Acad Sci U S A 91:3077–3081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ullrich SJ, Robinson EA, Law LW, Willingham M, Appella E (1986) A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc Natl Acad Sci U S A 83:3121–3125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Eden W (2018) Immune tolerance therapies for autoimmune diseases based on heat shock protein T-cell epitopes. Philos Trans R Soc Lond Ser B Biol Sci 373:20160531

    Article  Google Scholar 

  • van Herwijnen MJC, Wieten L, van der Zee RJ, van Kooten PJ, Wagenaar-Hilbers JP, Hoek A, den Braber I, Anderton SM, Singh M, Meiring HD, van Els CACM, van Eden W, Broere F (2012) Regulatory T cells that recognize a ubiquitous stress-inducible self-antigen are long-lived suppressors of autoimmune arthritis. Proc Natl Acad Sci U S A 109:14134–14139

    Article  PubMed  PubMed Central  Google Scholar 

  • Varol C, Vallon-Eberhard A, Elinav E, Aychek T, Shapira Y, Luche H, Fehling HJ, Hardt W, Shakhar G, Jung S (2009) Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31:502–512

    Article  CAS  PubMed  Google Scholar 

  • Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld J-C, Stockinger B (2008) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109

    Article  CAS  PubMed  Google Scholar 

  • Vercoulen Y, van Teijlingeni NH, de Kleer IM, Kamphuis S, Albani S, Prakken BJ (2009) Heat shock protein 60 reactive T cells in juvenile idiopathic arthritis: what is new? Arthritis Res Ther 11:231

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang S, Gao X, Shen G, Wang W, Li J, Zhao J, Wei Y, Edwards CK (2016) Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity. Sci Rep 6:24249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wegele H, Muller L, Buchner J (2004) Hsp70 and Hsp90 – a relay team for protein folding. Rev Physiol Biochem Pharmacol 151:1–44

    Article  CAS  PubMed  Google Scholar 

  • Wells AD, Rai SK, Salvato MS, Band H, Malkovsky M (1998) Hsp72-mediated augmentation of MHC class I surface expression and endogenous antigen presentation. Int Immunol 10:609–617

    Article  CAS  PubMed  Google Scholar 

  • Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5:761–772

    Article  CAS  PubMed  Google Scholar 

  • Yedavelli SP, Guo L, Daou ME, Srivastava PK, Mittelman A, Tiwari RK (1999) Preventive and therapeutic effect of tumor derived heat shock protein, gp96, in an experimental prostate cancer model. Int J Mol Med 4:243–251

    CAS  PubMed  Google Scholar 

  • Yi A, Yoon J, Yeo S, Hong S, English BK, Krieg AM (2002) Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J Immunol 168:4711–4720

    Article  CAS  PubMed  Google Scholar 

  • Yu W, Qu H, Cao G, Liu C, Deng H, Zhang Z (2017) MtHsp70-CLIC1-pulsed dendritic cells enhance the immune response against ovarian cancer. Biochem Biophys Res Commun 494:13–19

    Article  CAS  PubMed  Google Scholar 

  • Zanin-Zhorov A, Cahalon L, Tal G, Margalit R, Lider O, Cohen IR (2006) Heat shock protein 60 enhances CD4+ CD25+ regulatory T cell function via innate TLR2 signaling. J Clin Invest 116:2022–2032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou YJ, Messmer MN, Binder RJ (2014) Establishment of tumor-associated immunity requires interaction of heat shock proteins with CD91. Cancer Immunol Res 2:217–228

    Article  CAS  PubMed  Google Scholar 

  • Zou W (2005) Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5:263–274

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Our research is supported by grants from the Bloomberg-Kimmel Institute, the Melanoma Research Alliance, the National Institutes of Health (RO1AI099300, RO1AI089830 and R01AI137046), Department of Defense (PC130767); “Kelly’s Dream” Foundation, the Janey Fund, and the Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle. FP is a Stewart Trust Scholar.

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  1. Immunology and Hematopoiesis Division, Department of Oncology, Bloomberg-Kimmel Institute, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Anjali Ramaswamy, Ping Wei & Fan Pan

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  1. Anjali Ramaswamy
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  2. Ping Wei
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  3. Fan Pan
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Correspondence to Fan Pan .

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

    Alexzander A. A. Asea

  2. Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA

    Punit Kaur

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Ramaswamy, A., Wei, P., Pan, F. (2019). Diverse Roles of Heat Shock Proteins in Immune Activation and Tolerance: A Comprehensive Review of Mechanisms and Therapeutic Relevance. In: Asea, A., Kaur, P. (eds) Heat Shock Proteins in Signaling Pathways. Heat Shock Proteins, vol 17. Springer, Cham. https://doi.org/10.1007/978-3-030-03952-3_10

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