Heat shock proteins: to present or not, that is the question

The contribution of major histocompatibility complex (MHC) I and II to the adaptive immune response has been well documented. In 1996, Peter Doherty and Rolf Zinkernagel were awarded the Nobel Prize, for their fundamental observations concerning the genetic elements involved in specific antigen (Ag) recognition. These elements encode molecules that present self and non-self peptide fragments to both CD4+ and CD8+ cytolytic T lymphocytes (CTL). The recognition by Srivastava and coworkers that heat shock proteins (HSPs) might also present Ag in chemically induced sarcomas brought about many new questions concerning the central dogma of Ag processing and presentation. HSPs, in particular glucose-regulated peptide 94 (GRP94), HSP70 and to a lesser extent HSP90, bind peptides that are immunogenic in vitro and in vivo. There is mounting evidence that these HSP-peptide complexes provide alternative Ag-specific recognition in many systems. Whether a separate genetic program evolved in addition to MHC that increases the antigenic repertoire of the cell or if this newly observed function of HSP is predominantly a laboratory-based phenomena and/or a normal chaperone function of this family of proteins remains to be answered. Nevertheless, there are clinical therapeutic strategies that involve HSP-derived peptides isolated from various tumors that look extremely promising.