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CD91: a receptor for heat shock protein gp96

Nature Immunology volume 1, pages 151–155 (2000)Cite this article

Abstract

Antigen presenting cells (APCs) can take up exogenous antigenic peptides chaperoned by heat shock protein gp96 and re-present them through the endogenous pathway on their major histocompatibility class I molecules. The high efficiency of this process has been attributed previously to a receptor for gp96 on APCs. The CD91 molecule (also called α2-macroglobulin receptor or the low density lipoprotein–related protein) is shown here to be a cell surface receptor for the heat shock protein gp96. CD91 binds gp96 directly, rather than through another ligand for CD91. The previously known CD91 ligand, α2-macroglobulin, inhibits re-presentation of gp96-chaperoned antigenic peptides by macrophages, as do antibodies to CD91. As gp96 is exclusively intracellular and is released as a result of necrotic but not apoptotic cell death, we propose that CD91 acts as a sensor for necrotic cell death.

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Figure 1: Identification of an 80-kD protein as a putative gp96 receptor.
Figure 2: Antiserum to p80 detects an 80-kD molecule and inhibits re-presentation of gp96-chaperoned AH1 peptide by macrophage.
Figure 3: Protein microsequencing revealed that p80 is CD91.
Figure 4: α2-macroglobulin (α2M) and monoclonal antibody (mAb) to CD91 inhibit re-presentation of gp96-chaperoned AH1 peptide by APC.
Figure 5: CD91 as a sensor of necrotic cell death.

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Acknowledgements

Supported by NIH grants CA64394 and CA84479, and a research agreement with Antigenics Inc., in which P.K.S. has a significant financial interest. We thank S. Basu for sharing unpublished observations and for refining and making available the re-presentation assay, T. Matsutake, K. Anderson and R. Berlin for discussion and evaluation of experiments, and D. Ritsick for assistance with the cross-linking studies.

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Authors and Affiliations

  1. Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, 06030, CT, USA

    Robert J. Binder & Pramod K. Srivastava

  2. Department of Molecular Biotechnology, University of Washington, Seattle, 98195, WA, USA

    David K. Han

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Correspondence to Pramod K. Srivastava.

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Binder, R., Han, D. & Srivastava, P. CD91: a receptor for heat shock protein gp96. Nat Immunol 1, 151–155 (2000). https://doi.org/10.1038/77835

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