Immunological Properties of Heat Shock Proteins are Phylogenetically Conserved

  • Jacques Robert
  • Antoine Ménoret
  • Pramod K. Srivastava
  • Nicholas Cohen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 484)


Heat shock proteins (HSPs) serve as molecular chaperones of polypeptides transported between cell organelles, and contribute to the folding of nascent and altered proteins. A rapidly growing body of data suggests that at least in mammals, the HSPs 70 and gp96, are involved in immunity (review in Srivastava et al., 1998). Considering some analogy between MHC molecules and HSPs, it has been hypothesized that HSPs may have been forerunner presenting molecules, and that this primitive antigen presenting mechanism was integrated in the newly evolved MHC system (Srivastava and Heike, 1991). Structural similarities between hsp70 and major histocompatibility complex (MHC) class I peptide binding sites led Flajnik (1991) to a partially similar suggestion. Three characteristics of HSPs are reminiscent of MHC molecules (Table 1). First, these HSPs can physiologically associate with a large variety of antigenic peptides derived from cellular proteins. Second, after immunization with HSP-peptide complexes, T-cell immune responses are elicited against the chaperoned peptide. Finally, under certain circumstances (cell surface expression, cell death), these intracellular proteins end up in the extracellular compartment. Given the high degree of structural conservation of HSPs during evolution, their possible involvement in immune function, in general, and tumor immunity in particular, may be reflective of an ancient origin of HSPs that was contemporary with, or even antecedent to, the emergence of the vertebrate adaptive immune system that uses MHC presentation and restriction. In this review, we will examine the extent to which those immunological properties of HSPs found in mammals (peptide binding and chaperoning, adjuvanticity, immunogenicity) are phylogenetically conserved, and by extension, whether HSPs may be an evolutionary bridge between innate and adaptive immunity.

Table 1

HSP and MHC molecules have multiple features in common

HSP (gp96)


Very ancient (present in prokaryotes & eukaryotes)

Evolutionarily recent (arose in gnathostomes)

No polymorphism

Allelic polymorphism

Induced by IFN-γ, heat shock, glucose deprivation, viral infection

Expression is induced by IFN-γ

Binds peptides and unfolded proteins

Binds peptides

Mainly intracellular (cytosol or ER) but also at the surface of some cells

Expressed at the cell surface (most cells for class I, professional antigen-presenting cells for class II)

HSP-peptide complex can prime T-cells in solution (possibly also when expressed at the surface of some cells)

MHC-peptide complex can prime T-cell only when expressed at the surface of antigen-presenting cells


Major Histocompatibility Complex Heat Shock Protein Major Histocompatibility Complex Class Major Histocompatibility Complex Molecule Tumor Rejection Antigen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Agrawal, A., Eastamn, Q., and Schatz, D. (1998). Transposition mediated by Ragl and Rag2 and its implication for the evolution of the immune system. Nature 394: 744–751.PubMedCrossRefGoogle Scholar
  2. Altmeyer, A., Maki, R.G., Feldweg, A.M., Heike, M., Protopopov, V.P., Masur, S.K. and Srivastava, P. (1996). Tumor-specific cell surface expression of KDEL-containing, endoplasmic reticular heat shock protein gp96. Int. J. Cancer 69: 340–349.PubMedCrossRefGoogle Scholar
  3. Amato, R., Murray L., Wood, B., Savary, C., Tomasovic S., Srivastava P.K„ and Reitsma, D. (1999). ASCO meetingGoogle Scholar
  4. Anderson, S.L., Shen, T., Lou, J., Xing, L., Blachere, N.E., Srivastava, P. and Rubin B.Y. (1994). The endoplasmic reticular heat shock protein gp96 is transcriptionally upregulated in interferon-treated cells. J. Exp. Med. 180: 1565–1569.PubMedCrossRefGoogle Scholar
  5. Arnold, D., Faath, S., Rammensee, H. and Shild H. (1995). Cross-priming of minor histocompatibility antigen-specific cytotoxic T cells upon immunization with the heat shock protein gp96. J. Exp. Med. la 885–889.Google Scholar
  6. Bartl, S. (1998). What sharks can tell us about the evolution of MHC genes. Immunol. Rev. 166: 317–331.PubMedCrossRefGoogle Scholar
  7. Basu, S., Suto, R., Binder, J. and Srivastava, P. (1998). Heat-shock proteins as novel mediators of cytokine secretion by macrophages. Cell Stress & Chaperones 3 (suppl. 1), 11.Google Scholar
  8. Binder, J., Ménoret, A. and Srivastava, P. (1998). Receptor-dependent and receptor-independent representation of heat-shock protein-chaperoned peptides. Cell Stress & Chaperones 3 (suppl. 1), 2.Google Scholar
  9. Blachere, N.E., Li, Z., Chandawarkar, R.Y., Suto, R., Jaikaria, N.S., Basu, S., Udono, H and Srivastava, P. K. (1997). Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity. J. Exp. Med. 1k: 1315–1322.CrossRefGoogle Scholar
  10. Ciupitu, A., Peterson, M., O’Donnell, C., Williams, K., Jindal, S., Kiessling, R., and Welsh, M. (1998). Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity specific cytotoxic T lymphocytes. J. Exp. Med. 187: 685–691.PubMedCrossRefGoogle Scholar
  11. Clem, L.W., Bly, J. E., Wilson, M., Chinchar, V.G., Stuge, T., Barker, K., Luft, C., Rycyzyn, M., Hogan, R. J., van Lopik, T. and Miller, N. W. (1996). Fish immunology: The utility of immortalized lymphoid cells-a mini review. Vet. Immunol. Immunopath. 54: 137–144.CrossRefGoogle Scholar
  12. Cohen, N. 1968. Chronic skin graft rejection in the Urodela. I. A comparative study of the first-and second-set allograft reactions. J. Exp. Zool. 167:37–48.PubMedCrossRefGoogle Scholar
  13. Du Pasquier, L., and Flajnik, M. (1999). Origin and evolution of the vertebrate immune system. In Paul, W. E. ed., Fundamental Immunology, Fourth Edition p. 605–649. Raven Press New York.Google Scholar
  14. Du Pasquier L. and Robert J. (1992). In vitro growth of thymic tumor cell lines from Xenopus. Devel. Immunol. 2: 295–307.CrossRefGoogle Scholar
  15. Du Pasquier, L., Schwager, J., and Flajnik, M. F. (1989). The immune system of Xenopus. Annu. Rev. Immunol. 7: 251–275.CrossRefGoogle Scholar
  16. Flajnik, M.F., Canel, C., Kramer, J., and Kasahara, M. (1991). Which came first, MHC class I or class II? Immunogenetics E: 295–300.Google Scholar
  17. Flajnik, M., Kasahara, M., Shum, P., Salter-Cid, L., Taylor, A., and Du Pasquier L. (1993). A novel type of class I gene organization in vertebrates: a large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus. EMBO J.12: 4385–4495.PubMedGoogle Scholar
  18. Gupta, R. (1995). Phylogenetic analysis of the 90kK heat shock family of protein sequences and ab examination of the relationship among animals, plants, and fungi species. Mol. Biol. Evol. 12: 1063–1073.Google Scholar
  19. Hendrick, J.P. and Hartl, F.U. (1993). Molecular chaperone functions of heat-shock proteins. Annu. Rev. Biochem. í82:349–375.Google Scholar
  20. Hiom, K., Melek, M., and Gellert, M. (1998). DNA transposition by the RAG! and RAG2 proteins: a possible source of oncogenic translocation. Cell 24: 463–470.CrossRefGoogle Scholar
  21. Horton, T. L., Ritchie, P., Watson, M., and Horton, J. D. (1998). Natural cytotoxicity towards allogeneic tumour targets in Xenopus mediated by diverse splenocyte populations. Dev. Comp. Immunol. 22: 217–230.Google Scholar
  22. Kim, H.T, Nelson, EL, Clayburger, C., Sanjanwala, M., Sklar, J. and Krensky, A.M. (1995). Gamma delta T cell recognition of tumor Ig peptide. J. Immunol. 154; 1614–1623.PubMedGoogle Scholar
  23. Kobel, H.R. and Du Pasquier, L. (1977). Strains and species of Xenopus for immunological research. In: Developmental Immunology, Solomon, J.B. and Horton, J.D. Eds, (Amsterdam, ElsevierNorth-Holland), pp. 299–306.Google Scholar
  24. Kock, G., Smith, M., Macer, D., Webster, P., and Mortara, R. (1986). Endoplasmic reticulum contains a common, abundant calcium-binding glycoprotein, endoplasmin.J. Cell. Sci. 86: 217–232.Google Scholar
  25. Krone, P.H. and Sass, J. (1994). Hsp90a and hsp90b genes are present in the zebrafish and are differentially regulated in developing embryos. Biochem. Biophys. Res. Comm. 204: 746–752.Google Scholar
  26. Lammert, E., Arnold, D., Nijenhuis, M., Momburg, F., Hammerliing, G., Brunner, J., Stevanovic, S., Rammensee, H. and Schild, H. (1997). The endoplasmic reticulum-resident stress protein gp96 binds peptides translocated by TAP. Eur. J. Immunol. 21: 923–927.CrossRefGoogle Scholar
  27. Lewis, J., Janestzki, S., Livingston, P., Desantis, D., Williams, L., Klitnstra, W., Reitman, D., Hougaton A., Srivastava, P., and Bronnan, J. (1999). ASCO meeting.Google Scholar
  28. Marchalonis, J., Schluter, S., Bernstein, R. and Hohman, V. (1998). Antibodies of sharks: revolution and evolutions. Immunol. Rev. 166: 103–122.PubMedCrossRefGoogle Scholar
  29. Mayr, E. (1997). This is biology. The science of the living world. The Belknap press of Harvard University press. Cambridge MS. 323 pp.Google Scholar
  30. Matzinger, P. (1994). Tolerance, danger, and the extended family. Ann. Rev. Immunol. 12: 991–1045.CrossRefGoogle Scholar
  31. Ménoret, A., Peng, P. and Srivastava, P.K. (1999). Association of peptides with the heat shock protein gp96 occurs in vivo and not post cell lysis. Bioch. Biophys.Res. Corn. (In press)Google Scholar
  32. Moore, S.K., Kozak, C., Robinson, E.A., Ullrich, S.J. and Appella, E. (1989). Mutine 86- and 84-kDa heat shock proteins, cDNA sequences, chromosome assignments, and evolutionary origins. J. Biol. Chem. 264: 5343–5351.PubMedGoogle Scholar
  33. Morimoto, E., Tissiere, A., and Georgopoulos, eds (1994). The biology of heat shock proteins and molecular chaperones. Cold Spring Harbor Laboratory, Cold Sprong Harbor, NY.Google Scholar
  34. Multhoff, G., Botzler, C., Wiesnet, M., Müller, E., Meier, T., Wilmann, W., and Issels, R. (1995). A stress-inducible 72-kDa heat-shock protein (hsp72) is expressed on the surface of human tumor cells, but not on normal cells. Int. J. Cancer 61: 272.PubMedCrossRefGoogle Scholar
  35. Multhoff, G., Botzler, C., Jennen, L., Schmidt, J., Ellwart, J., and Issels, R. (1997). Heat shock protein 72 on tumor cells a recognition structure for natural killer cells. J. Immunol. 158: 4341–4350.PubMedGoogle Scholar
  36. Nicchitta CV. (1998). Biochemical, cell biological and immunological issues surrounding the endoplasmic reticulum chaperone GRP94/gp96. Current Op. Immunol; 11 103–109.Google Scholar
  37. Nieland, T.J.F., M.C.A. Tan, M. van Muijen, F. Koning, A. Kruisbeek, and G.M. van Bieck., (1996) Isolation of an immunodominant viral peptide that is enbdogenously bound to the stress protein gp96/grp94. Proc. Natl. Acad. Sci.(USA) 23: 6135–6139.CrossRefGoogle Scholar
  38. O’Brien, R., Happ, M., Dallas, A., Palmer, E., Kubo, R. and Born, W. (1989). Stimulation of a major subset of lymphocytes expressing T cell receptor gamma delta by an antigen derived from Mycobacterium tuberculosis. Cell 51: 667–674.CrossRefGoogle Scholar
  39. Parham, P. (1994). The rise and fall of great class I genes. Semin. Immunol. ¢: 373–382Google Scholar
  40. Parham, P. Ed. (1998). Immune system of ectothermic vertebrates. Immunol. Rev. 166. 384 pp.Google Scholar
  41. Robert, J. and Du Pasquier L. (1996). Xenopus lymphoid tumor cell lines. In: Manual of Immunological Methods ed. I. Lefkovitz. Academic Press, pp. 2367–237.CrossRefGoogle Scholar
  42. Robert, J., Guiet, C. and Du Pasquier L. (1994). Lymphoid tumors of Xenopus laevis with different capacities for growth in larvae and adults. Devel. Immunol. 3: 297–307.Google Scholar
  43. Robert, J., Guiet, C. and Du Pasquier L. (1995). Ontogeny of the alloimmune response against transplanted tumor in Xenopus laevis. Differentiation 52: 135–144.CrossRefGoogle Scholar
  44. Robert, J., Guiet C., Cohen, N., and Du Pasquier L. (1997). Effects of thymectomy and tolerance induction on tumor immunity in adult Xenopus laevis. Internat. J. Canc. 70: 330–334.Google Scholar
  45. Robert, J., Ménoret, A., Srivastava, P. and Cohen, N. 1998. The tumor-specific immunogenicity of the heat-shock protein gp96 is conserved during evolution. Cell Stress & Chaperones 3:suppl.1, 22.Google Scholar
  46. Robert, J., and Cohen, N. (1998). Evolution of immune surveillance. Immunol. Rev. 166:231–243.PubMedCrossRefGoogle Scholar
  47. Robert, J., Ménoret, A., and Cohen, N. (1999). Cell surface expression of the endoplasmic reticular heat shock protein gp96 is phylogenetically conserved. J. Immunol. (In press).Google Scholar
  48. Robert, J., Ménoret, A., Cohen N., and Srivastava, A. (1999). The immunological properties of the heat shock protein gp96 are conserved across phylogenetically distant species. (submitted).Google Scholar
  49. Salter-Cid, L. and Flajnik, M. (1995). Evolution and developmental regulation of the major histocompatibility complex. Crit. Rev. Immunol. 35: 31–75.Google Scholar
  50. Salter-Cid, L., Nonaka, M., and Flajnik, MF. (1998). Expression of MHC class Ia and class lb during ontogeny: high expression in epithelia and coregulation of class Ia and lmp7 genes. J. Inununol.: 2853–61Google Scholar
  51. Sammut, B., Laurens, V., and Toumefier, A. (1997). Isolation of Mhc class I cDNAs from the axolotl Ambystoma mexicanum. Immunogenetics 45: 285–294.PubMedCrossRefGoogle Scholar
  52. Srivastava, P.K., Deleo, A., and Old, L.J. (1986). Tumor rejection antigens of chemically induced sarcomas of inbred mice. Proc. Natl. Acad. Sci. USA 83: 3407–3411.PubMedCrossRefGoogle Scholar
  53. Srivastava, P.K and Heike, M. (1991). Tumor-specific immunogenicity of stress-induced proteins: convergence of two evolutionary pathways of antigen presentation? Sem. Immunol. 3: 57–64.Google Scholar
  54. Srivastava„ P.K and Maki, R.G. (1991). Stress-induced proteins in immune response to Cancer. Curr. Top. Microbiol. Immunol. 167: 109–121.PubMedCrossRefGoogle Scholar
  55. Srivastava, P.K., Udono, H., Blachere, N.E. and Li, Z. (1994). Heat shock proteins transfer peptides during antigen processing and CTL priming. Immunogenetics 39: 93–98.PubMedCrossRefGoogle Scholar
  56. Srivastava, P.K. (1997). Purification of heat shock protein-peptide complexes for use in vaccination against cancers and intracellular pathogens. Immunol. Methods Manual 9.11: 737–747.Google Scholar
  57. Srivastava PK., Ménoret A., Basu S., Binder RJ., McQuade KL. 1998. Heat shock proteins come of age: primitive functions acquire new roles in an adaptive world. Immunity. 8:657–65PubMedCrossRefGoogle Scholar
  58. Suto, R. and Srivastava, P.K. (1995). A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269: 1585–1588.PubMedCrossRefGoogle Scholar
  59. Tamura, Y., Tsuboi, N., Sato, N. and Kibuchi, K. (1993). 70-kDa heat-shock cognate protein is a transformation-associated antigen and a possible target for host’s anti-tumor immunity. J. Immunol. 151: 5516–5524.PubMedGoogle Scholar
  60. Tamura, Y, Peng, P, Liu, K, Daou, M and Srivastava, P.K. (1997) Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278: 117–119.PubMedCrossRefGoogle Scholar
  61. Takemoto, H., Yoshimori, T., Yamamoto, A., Myiata, Y., Yahara, I., Inoue, K., and Tashiro, Y. (1992). Heavy chain binding protein (BiP/GRP78) and endoplasmin are exported from the endoplasmic reticulum in rat exocrine pancreatic cells, similar to protein disulfide-isomerase. Arch. Biochem. Biophysics 296: 129–134.CrossRefGoogle Scholar
  62. Udono, H. and Srivastava, P.K. (1993). Heat shock protein 70-associated peptides elicit specific cancer immunity. J. Exp. Med. 178: 1391–1396.PubMedCrossRefGoogle Scholar
  63. Udono, H. and Srivastava, P.K. (1994). Comparison of tumor-specific immunogenicities of stress-induced proteins gp96, hsp90 and hsp70. J. Immunol. 5: 5398–5403.Google Scholar
  64. Udono, H., Levey, D.L. and 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. Proc. Natl. Acad. Sci. USA 21: 3077–3081.CrossRefGoogle Scholar
  65. Ullrich, S., Robinson, A., Law, W., Willingham, M., and Appella E. (1986). A mouse tumor-specific transplantation antigen is a heat shock-related protein. Proc. Natl. Acad. Sci. USA 83: 3121–3128.PubMedCrossRefGoogle Scholar
  66. Van Buskirk, A., Crump, B., Margoliash, E. and Pierce, S. (1989). A peptide-binding protein having a role in antigen presentation is a member of the hsp70 family. J. Exp. Med. ID: 1799–1809.Google Scholar
  67. Wassenberg, J., Dezfulian, C., and Nicchitta, C. (1999). Receptor mediated and fluid phase pathways for internalization of the ER Hsp90 chaperone GRP94 in murine macrophages. J. Cell Science 112: 2167–2175.PubMedGoogle Scholar
  68. Wells, A., Rai, S., Salvato, M., Band, H., and Malkovsky, M. (1998). Hsp 72-mediated augmentation of MHC class I surface expression and endogeneous antigen presentation. Int. Immunol. 10: 609–617.PubMedCrossRefGoogle Scholar
  69. Wiest, D., Bhandoola, A., Punt, J., Kreibich, G., McKean, D. and Singer, A. (1997). Incomplete endoplasmic reticulum (ER) retention in immature thymocytes as revealed by surface expression of “ER-resident” molecular chaperones. Proc. Natl. Acad. Sci. USA 91. 1884–1889.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Jacques Robert
    • 1
  • Antoine Ménoret
    • 2
  • Pramod K. Srivastava
    • 2
  • Nicholas Cohen
    • 1
  1. 1.Department of Microbiology and ImmunologyUniversity of Rochester School of Medicine and DentistryRochester
  2. 2.Center for Immunotherapy of Cancer and Infectious DiseasesUniversity of Connecticut School of MedicineFarmington

Personalised recommendations