Heat shock proteins (HSPs) such as gp96 are released from cells as a result of necrotic cell death. The ability of endogenous HSP-
peptide complexes to elicit
antigen-specific T cells requires representation of the chaperoned
peptides by antigen-presenting cells. Re-presentation requires the uptake of HSP-
peptide complexes through a receptor, suggested to be the
low-density lipoprotein receptor-related
protein or CD91. We have used
short interfering RNA for CD91 to show that, as antigen-presenting cells lose expression of CD91, their re-presenting ability undergoes a corresponding and dramatic decline. Furthermore, as the cells recover from extinction of CD91 expression, they regain the ability to re-present
peptides. The ability of cells to bind
alpha(2) macroglobulin, a previously known CD91
ligand, or HSP gp96, and their ability to process
peptides chaperoned by
alpha(2) macroglobulin, undergo identical variations. These results have been obtained from studies in vitro and from an assay that measures re-presentation in vivo. In additional studies in vivo, protective
tumor immunity elicited by
tumor-derived gp96-peptide complexes is shown to be abrogated by anti-CD91
antisera. These studies show that CD91 is essential for re-presentation of gp96-chaperoned
peptides by MHC molecules and have an important bearing on the mechanism of immunogenicity of necrotic cells.