The messenger and the message: gp96 (GRP94)-peptide interactions in cellular immunity

Abstract

Vaccination of mice with tumor-derived stress proteins, such as Hsp70 and gp96 (GRP94), can elicit antitumor immune responses, yielding a marked suppression of tumor growth and metastasis. The molecular basis for this response is proposed to reflect a peptide-binding function for these proteins. In this view, stress proteins bind the antigenic peptide repertoire of their parent cell, and when provided to the immune system, tumor-derived stress proteinpeptide complexes are processed by antigen-presenting cells (APCs) to yield the subsequent activation of tumordirected cytotoxic T lymphocyte activity. This model predicts that stress proteins, whose primary intracellular function concerns the proper folding and assembly of nascent polypeptides, intersect with the cellular pathways responsible for the generation, processing, or assembly (or all) of peptide antigens onto nascent major histocompatability class I molecules. Recent insights into the pathways for peptide generation now allow this hypothesis to be critically examined, which is the subject of this review.

Specific Immunogenicity of Heat Shock Protein gp96 Derives from Chaperoned Antigenic Peptides and Not from Contaminating Proteins

“…An argument has been made, without any accompanying evidence, that gp96 is such an excellent adjuvant for any proteins present in the same solution as gp96 and that this adjuvanticity of gp96 is responsible for eliciting immune response to "contaminating proteins" (21)(22)(23)(24). The corresponding evidence with respect to peptides is clear; immunization with mixtures of gp96 and peptides does not elicit immunity specific for the peptide.…”

“…Peptide-binding sites of hsp70 (17,18) and gp96 (19,20) have been demonstrated by crystallography and modeling studies. Nonetheless, the notion that specific immunogenicity of HSP preparations derives from peptides noncovalently and physiologically associated with the HSP molecule has been questioned recently (21)(22)(23)(24). The questioning is based on the idea that HSP preparations are contaminated with trace amounts of other cellular proteins and that this trace contamination and not the HSP-chaperoned peptides is responsible for the specific immunogenicity of the HSP.…”

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

“…102,105,106,118,120,121 Although the immunological properties of Gp96 were documented extensively, the assumption that the specific immunogenic character of HSP preparations originates from peptides that are noncovalently and physiologically associated with the HSP molecule has been questioned. 118,[122][123][124][125][126] The studies of Binder et al were in favor of this assumption. Gp96 was purified from b-galactosidase-transfected mastocytoma cells.…”

Chaperone-related immune dysfunction: an emergent property of distorted chaperone networks

“…[6], are involved in antigen cross-presentation and the consequent antiviral and anticancer immune response. Although the extent of chaperone-mediated antigenic peptides in cross-presentation has been debated [7,8], the necessity and sufficiency of peptides chaperoned by Hsps for antigen cross-priming of CD8 C T cells was recently shown [9,10]. However, the involvement of chaperones in cross-priming might also occur at the proteasomal substrate level [11] or by (chaperoneassisted) autophagy inducing MHC class II presentation of intracellular antigens [12].…”