Abstract
Pathogens or pathogen-associated molecular patterns can signal to cells of the innate immune system and trigger effective adaptive immunity. However, relatively little is known about how the innate immune system detects tissue injury or necrosis. Evidence suggests that the release of heat-shock proteins (HSPs) may provide adjuvant-like signals, but the ability of HSPs to promote activation or tolerance in vivo has not been addressed. In this study we show that Hsp70 promotes dendritic cell (DC) function and, together with antigen, triggers autoimmune disease in vivo.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Heath, W.R. & Carbone, F.R. Cross-presentation, dendritic cells, tolerance and immunity. Annu. Rev. Immunol. 19, 47–64 (2001).
Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
Janeway, C.A., Jr. & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Diehl, L. et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat. Med. 5, 774–779 (1999).
Sotomayor, E.M. et al. Conversion of tumor-specific CD4+ T-cell tolerance to T-cell priming through in vivo ligation of CD40. Nat. Med. 5, 780–787 (1999).
Garza, K.M. et al. Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 191, 2021–2027 (2000).
Bansal-Pakala, P., Jember, A.G. & Croft, M. Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat. Med. 7, 907–912 (2001).
Ehl, S. et al. Viral and bacterial infections interfere with peripheral tolerance induction and activate CD8+ T cells to cause immunopathology. J. Exp. Med. 187, 763–774 (1998).
Schuurhuis, D.H. et al. Immature dendritic cells acquire CD8+ cytotoxic T lymphocyte priming capacity upon activation by T helper cell-independent or -dependent stimuli. J. Exp. Med. 192, 145–150 (2000).
Mauri, C., Mars, L.T. & Londei, M. Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process. Nat. Med. 6, 673–679 (2000).
Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).
Basu, S., Binder, R.J., Suto, R., Anderson, K.M. & Srivastava, P.K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. Int. Immunol. 12, 1539–1546 (2000).
Sauter, B. et al. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells. J. Exp. Med. 191, 423–434 (2000).
Chen, W., Syldath, U., Bellmann, K., Burkart, V. & Kolb, H. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J. Immunol. 162, 3212–3219 (1999).
Asea, A. et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6, 435–442 (2000).
Kol, A., Lichtman, A.H., Finberg, R.W., Libby, P. & Kurt-Jones, E.A. 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. 164, 13–17 (2000).
Ohashi, K., Burkart, V., Flohe, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).
Moroi, Y. et al. Induction of cellular immunity by immunization with novel hybrid peptides complexed to heat shock protein 70. Proc. Natl. Acad. Sci. USA 97, 3485–3490 (2000).
Singh-Jasuja, H. et al. The heat shock protein gp96 induces maturation of dendritic cells and down-regulation of its receptor. Eur. J. Immunol. 30, 2211–2215 (2000).
Cho, B.K. et al. A proposed mechanism for the induction of cytotoxic T lymphocyte production by heat shock fusion proteins. Immunity 12, 263–272 (2000).
Kuppner, M.C. et al. 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. Eur. J. Immunol. 31, 1602–1609 (2001).
Binder, R.J., Anderson, K.M., Basu, S. & Srivastava, P.K. Cutting edge: heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo. J. Immunol. 165, 6029–6035 (2000).
Wang, Y. et al. CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15, 971–983 (2001).
Ohashi, P.S. et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317 (1991).
Kyburz, D. et al. T cell immunity after a viral infection versus T cell tolerance induced by soluble viral peptides. Eur. J. Immunol. 23, 1956–1962 (1993).
Chiller, J.M. & Weigle, W.O. Termination of tolerance to human gamma globulin in mice by antigen and bacterial lipopolysaccharide (endotoxin). J. Exp. Med. 137, 740–750 (1973).
Bausinger, H. et al. Endotoxin-free heat-shock protein 70 fails to induce APC activation. Eur. J. Immunol. 32, 3708–3713 (2002).
Gao, B. & Tsan, M.F. Endotoxin contamination in recombinant human heat shock protein 70 (Hsp70) preparation is responsible for the induction of tumor necrosis factor α release by murine macrophages. J. Biol. Chem. 278, 174–179 (2003).
Srivastava, P.K. Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Methods 12, 165–171 (1997).
Ridge, J.P., Di Rosa, F. & Matzinger, P. A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393, 474–478 (1998).
Bennett, S.R. et al. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393, 478–480 (1998).
Schoenberger, S.P., Toes, R.E., van der Voort, E.I., Offringa, R. & Melief, C.J. T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393, 480–483 (1998).
Akira, S., Takeda, K. & Kaisho, T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat. Immunol. 2, 675–680 (2001).
Basu, S., Binder, R.J., Ramalingam, T. & Srivastava, P.K. CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin. Immunity 14, 303–313 (2001).
Asea, A. et al. Novel signal transduction pathway utilized by extracellular HSP70: role of toll-like receptor (TLR) 2 and TLR4. J. Biol. Chem. 277, 15028–15034 (2002).
Vabulas, R.M. et al. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107–15112 (2002).
Srivastava, P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu. Rev. Immunol. 20, 395–425 (2002).
Blachere, N.E. et al. Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 186, 1315–1322 (1997).
Suzue, K., Zhou, X., Eisen, H.N. & Young, R.A. Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway. Proc. Natl. Acad. Sci. USA 94, 13146–13151 (1997).
Ciupitu, A.M. et al. Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes. J. Exp. Med. 187, 685–691 (1998).
Liu, B. et al. Cell surface expression on an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune disease. Proc. Natl. Acad. Sci. USA (in the press).
Melcher, A. et al. Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Nat. Med. 4, 581–587 (1998).
Somersan, S. et al. Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells. J. Immunol. 167, 4844–4852 (2001).
Breloer, M., Fleischer, B. & von Bonin, A. In vivo and in vitro activation of T cells after administration of Ag-negative heat shock proteins. J. Immunol. 162, 3141–3147 (1999).
Asea, A., Kabingu, E., Stevenson, M.A. & Calderwood, S.K. HSP70 peptide-bearing and peptide-negative preparations act as chaperokines. Cell Stress Chaperones 5, 425–431 (2000).
Binder, R.J., Han, D.K. & Srivastava, P.K. CD91: a receptor for heat shock protein gp96. Nat. Immunol. 1, 151–155 (2000).
Becker, T., Hartl, F.U. & Wieland, F. CD40, an extracellular receptor for binding and uptake of Hsp70-peptide complexes. J. Cell Biol. 158, 1277–1285 (2002).
Schulz, O. et al. CD40 triggering of heterodimeric IL-12 p70 production by dendritic cells in vivo requires a microbial priming signal. Immunity 13, 453–462 (2000).
Hemmi, H. et al. A Toll-like receptor recognizes bacterial DNA. Nature 408, 740–745 (2000).
Kaisho, T., Takeuchi, O., Kawai, T., Hoshino, K. & Akira, S. Endotoxin-induced maturation of MyD88-deficient dendritic cells. J. Immunol. 166, 5688–5694 (2001).
Alexopoulou, L., Holt, A.C., Medzhitov, R. & Flavell, R.A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732–738 (2001).
Nguyen, L.T. et al. Tumor growth enhances cross-presentation leading to limited T cell activation without tolerance. J. Exp. Med. 195, 423–435 (2002).
Lutz, M.B. et al. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J. Immunol. Methods 223, 77–92 (1999).
Chan, V.S., Wong, C. & Ohashi, P.S. Calcineurin Aα plays an exclusive role in TCR signaling in mature but not in immature T cells. Eur. J. Immunol. 32, 1223–1229 (2002).
Acknowledgements
This study was supported by a Canadian Institute for Health Research operating grant and CANVAC Network Centres of Excellence. D.G.M. is the recipient of a Canadian Diabetes Association Fellowship. K.M.G. is supported by National Institutes of Health grants S06GM08012 and SG12RR08124. Z.L. is supported in part by NIH grant CA90337. P.S.O. holds a Canada Research Chair in Infection and Immunity.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Millar, D., Garza, K., Odermatt, B. et al. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat Med 9, 1469–1476 (2003). https://doi.org/10.1038/nm962
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm962
This article is cited by
-
Introducing Molecular Chaperones into the Causality and Prospective Management of Autoimmune Hepatitis
Digestive Diseases and Sciences (2023)
-
Antigen Cross-Presentation and Heat Shock Protein-Based Vaccines
Archivum Immunologiae et Therapiae Experimentalis (2016)
-
Tumor-derived inducible heat-shock protein 70 (HSP70) is an essential component of anti-tumor immunity
Oncogene (2015)
-
Myeloid-related protein 8 induces self-tolerance and cross-tolerance to bacterial infection via TLR4- and TLR2-mediated signal pathways
Scientific Reports (2015)
-
The oxidation of HSP70 is associated with functional impairment and lack of stimulatory capacity
Cell Stress and Chaperones (2014)