Molecular chaperones and cancer vaccines

Recently emerging evidence indicates that the heat shock proteins (HSP) gp96, hsp90, hsp70 associate with antigenic peptides derived from cellular proteins. This evidence forms the basis of the following two hypothess: 1) that HSPs constitute a relay line in which the peptides, after generation in the cytosol by the action of proteases are transfered from one HSP to another, until they are finally accepted by MHC class I molecules in the endoplasmic reticulum, and 2) that the binding of peptides by HSPs consitutes a key step in the priming of cytotoxic T lymphocytes (TCTLs) in vivo. The following chain of events is suggested: HSPs are released from virus-infected cells or tumor cells in vivo during lysis of cells during infection or by the action of antibodies or nonspecific effectors. The HSPs, which are now complexed with antigenic peptides derived form the cognates cells, are taken up by macrophage or other specialised antigen presenting cells, possibley by a receptor mediated mechanism. The HSP-borne peptide is then routed to the endogenous presentation pathway in the antigen-presenting cell and is displayed in the context of that cell's MHC class I. Where it is finally recognised by the precursor CTLs. Thus it is suggested that as with antigen presentation by MHC class II molecules, presentation by MHC class I molecules is also carried out primarily by the host antigen-presenting cells. This mechanism explains the phenomernon of cross-priming and has implications for the development of immunological strategies against cancer and infectious diseases.