Essential role of CD91 in re-presentation of gp96-chaperoned peptides.
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.
Binder
Robert J
RJ
Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.
Srivastava
Pramod K
PK
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002460:Cell Line; D006023:Glycoproteins / Q000502:physiology*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D018832:Molecular Chaperones / Q000502:physiology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000502:physiology*
D015703:Antigens, CD; D006023:Glycoproteins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018832:Molecular Chaperones; D010455:Peptides