Heat Shock Proteins Come of Age: Primitive Functions Acquire New Roles in an Adaptive World

During the analysis of representation of HSP-peptide complexes by APCs, another facet of HSP-APC interaction came to light. Exposure of APCs to gp96 preparations was observed to lead to stimulation of APCs to secrete low levels of cytokines regardless of the peptides associated with gp96 (Suto and Srivastava 1995xA mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Suto, R and Srivastava, P.K. Science. 1995; 269: 1585–1588Crossref | PubMedSee all ReferencesSuto and Srivastava 1995; Figure 3Figure 3). This was surprising but consistent with the observation that immunization with cancer-derived HSP-peptide complexes elicits, in addition to the CD8+ and CD4+ T cell response, an NK response that is crucial for eliciting protective immunity (Tamura et al. 1997xImmunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Tamura, Y, Peng, P, Kang, L, Daou, M, and Srivastava, P.K. Science. 1997; 278: 117–120Crossref | PubMed | Scopus (572)See all ReferencesTamura et al. 1997). In light of the fact that HSPs are abundant components of pathogens as well as hosts, this observation may indicate a basic role for HSP-APC interaction in innate immunity in addition to the crucial role of such interactions in adaptive, peptide-dependent immunity discussed thus far (73xHeat shock proteins transfer peptides during antigen processing and CTL priming. Srivastava, P.K, Udono, H, Blachere, N.E, and Li, Z. Immunogenetics. 1994; 39: 93–98Crossref | PubMed | Scopus (456)See all References, 81xCellular requirements for tumor-specific immunity elicited by heat shock proteins (tumor rejection antigen gp96 primes CD8+ T cells in vivo) . Udono, H, Levey, D.L, and Srivastava, P.K. Proc. Natl. Acad. Sci. USA. 1994; 91: 3077–3081Crossref | PubMedSee all References, 75xA mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Suto, R and Srivastava, P.K. Science. 1995; 269: 1585–1588Crossref | PubMedSee all References). Contemplation of these ideas leads to some interesting insights. HSPs are among the most primitive proteins in living systems, and macrophage-like cells of one kind or another are present in the earliest multicellular living systems (Beck and Habicht 1996xImmunity and invertebrates. Beck, G and Habicht, G.S. Sci. Am. 1996; 275: 60–63Crossref | PubMedSee all ReferencesBeck and Habicht 1996). It is conceivable that in a less polymorphic era, when adaptive immune response was but a distant gleam in the evolutionary eye, the interaction of HSPs with macrophage-like cells, leading to stimulation of the macrophage-like cells to secrete IL-1 and other messengers, was the primary “innate” defense mechanism. As HSPs are the most abundant soluble molecules in cells, they can be reasonably expected to be the most reliable messengers of cell death or, at any rate, cell lysis, which would result if the organism were in stress or danger, e.g., being consumed by a predator. This chain of events would also explain the otherwise strange presence of a surface receptor for HSPs, which are normally intracellular. In this view, the HSPs would have been transformed from being protectors of cells from cellular stress in the single-celled organisms to being messengers of stress and protectors against such stress in the first multicellular organisms or, at any rate, among those in which a differentiated macrophage-like cell had evolved. By all accounts, this happened quite early, as phagocytes of echinoderms, mollusks, annelids, and tunicates had already acquired the ability to secrete IL-1 like molecules (seeOttaviani and Franceschi 1997xThe invertebrate phagocytic immunocyte (clues to a common evolution of immune and neuroendocrine systems) . Ottaviani, E and Franceschi, C. Immunol. Today. 1997; 18: 169–174Abstract | Full Text PDF | PubMed | Scopus (130)See all ReferencesOttaviani and Franceschi 1997). From this initial point, it is relatively straightforward to see how the HSP-APC interaction could have been incorporated into future versions of the developing defense mechanisms until, with the arrival of specific immunity and its paraphernalia of specificity of peptide-binding and T cell receptors, the primal peptide-binding proteins, i.e., the HSPs, would become accessories in antigen presentation by MHC molecules. The evolutionary implications of a convergence of the peptide-binding functions of the HSPs and the MHC molecules has been discussed in detail elsewhere (Srivastava and Heike 1991xTumor-specific immunogenicity of stress-induced proteins (convergence of two evolutionary pathways of antigen presentation?) . Srivastava, P.K and Heike, M. Semin. Immunol. 1991; 3: 57–64PubMedSee all ReferencesSrivastava and Heike 1991).In the proposed role of HSPs as harbingers of cell death and, therefore, of danger to an organism (seeMatzinger 1994xTolerance, danger, and the extended family. Matzinger, P. Annu. Rev. Immunol. 1994; 12: 991–1045Crossref | PubMedSee all ReferencesMatzinger 1994), a kind of death that results in an encounter of HSPs with the immune system will be more productive, i.e., communicative of danger, and protective than a “silent death” that does not lead to HSP-APC interaction. It is therefore our belief that immunogenicity of cells, infectious agents, and cancers is defined to a significant degree upon the extent to which cell death leads to induction of HSPs and consequent HSP-APC interaction. Studies that show a cosegregation of immunogenicity of cancers with the expression of molecules of the hsp60 and hsp70 family (39xCo-segregation of tumor immunogenicity with expression of inducible but not constitutive hsp70 in rat colon carcinomas. Menoret, A, Patry, Y, Burg, C, and Le Pendu, J. J. Immunol. 1995; 155: 740–747PubMedSee all References, 85xRestoration of MHC class I surface expression and endogenous antigen presentation by a molecular chaperone. Wells, A.D, Rai, S.K, Salvato, M.S, Band, H, and Malkovsky, M. Scand. J. Immunol. 1997; 45: 605–612Crossref | PubMedSee all References, 38xTumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Melcher, A, Todryk, A, Hardwick, N, Ford, M, Jacobson, M, and Vile, R.G. Nat. Med. 1998; 4: 581–587Crossref | PubMed | Scopus (368)See all References) are consistent with this belief. It may be tempting in this context to imagine that immunologically unproductive and productive modes of death will correlate neatly with apoptotic and necrotic types of death; however, recent results indicate that this is not necessarily so (7xProcessing of engulfed apoptotic bodies yields T cell epitopes. Bellone, M, Iezzi, G, Rovere, P, Galati, G, Ronchetti, A, Protti, M.P, Davoust, J, Rugarli, C, and Manfredi, A.A. J. Immunol. 1997; 159: 5391–5399PubMedSee all References, 1xDendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Albert, M.L, Sauter, B, and Bhardwaj, N. Nature. 1998; 392: 86–89Crossref | PubMed | Scopus (1839)See all References, 38xTumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression. Melcher, A, Todryk, A, Hardwick, N, Ford, M, Jacobson, M, and Vile, R.G. Nat. Med. 1998; 4: 581–587Crossref | PubMed | Scopus (368)See all References). Other factors yet to be discovered must influence the immunological productivity of dying cells. In any case, it is safe to suggest that the recent fascination of immunologists with death has atavistic origins in the evolutionary past, when the presence of extracellular HSPs signaled physical disintegration.*To whom correspondence should be addressed (e-mail: srivastava@nso2.uchc.edu).