Essential role of CD91 in re-presentation of gp96-chaperoned peptides

Abstract

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 α 2 macroglobulin, a previously known CD91 ligand, or HSP gp96, and their ability to process peptides chaperoned by α 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.