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Roles of heat-shock proteins in innate and adaptive immunity

Nature Reviews Immunology volume 2, pages 185194 (2002) | Download Citation

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Abstract

Heat-shock proteins (HSPs) are the most abundant and ubiquitous soluble intracellular proteins. In single-cell organisms, invertebrates and vertebrates, they perform a multitude of housekeeping functions that are essential for cellular survival. In higher vertebrates, their ability to interact with a wide range of proteins and peptides — a property that is shared by major histocompatibility complex molecules — has made the HSPs uniquely suited to an important role in organismal survival by their participation in innate and adaptive immune responses. The immunological properties of HSPs enable them to be used in new immunotherapies of cancers and infections.

Key points

  • Heat-shock proteins (HSPs) are the most abundant group of intracellular molecules and are present in all cells of all organisms.

  • Some HSPs (gp96, HSP90, HSP70, HSP110, GRP170 and calreticulin) are peptide-binding proteins.

  • The HSP-chaperoned peptides are derived from a variety of cellular proteins. The HSP–peptide complexes that are purified from a cell therefore represent the peptide fingerprint of that cell.

  • HSP–peptide complexes that are purified from cancers contain the peptides derived from normal proteins, but also peptides derived from tumour antigens. Similarly, HSP–peptide complexes purified from cells infected with viruses or other pathogens contain pathogen-derived peptides, as well as normal peptides.

  • Immunization of mammals with HSP–peptide complexes elicits potent CD8+ and CD4+ T-cell responses against the HSP-chaperoned peptides. The response is restricted, however, to the foreign or mutated peptides; HSP-associated normal self-peptides do not elicit autoimmune responses.

  • Femtomoles of peptides, if chaperoned by HSPs, are immunogenic. Unchaperoned peptides or peptides that are chaperoned by other proteins do not elicit T-cell responses even at quantities that are higher by several logarithms.

  • The secret of the extraordinary immunogenicity of HSPs lies in a receptor on antigen-presenting cell CD91, which is also the receptor for serum protein α2 macroglobulin.

  • HSP-chaperoned peptides enter the macrophage/dendritic cells through CD91 and are processed and presented by the MHC class I and MHC class II molecules, resulting in the consequent stimulation of CD8+ and CD4+ T cells. At the same time, the HSP–dendritic-cell interaction through CD91 and other receptors leads to maturation of dendritic cells and secretion of an array of pro-inflammatory cytokines.

  • Through their interaction with macrophage and dendritic cells, HSPs are therefore able to stimulate peptide-specific (adaptive), as well as non-specific (innate), components of the immune response.

  • The ability of HSPs to chaperone antigenic peptides and to interact with dendritic cells has led to a new generation of prophylactic and therapeutic candidate vaccines against cancers and infectious diseases.

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  1. Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, Connecticut 06030-1601, USA. srivastava@nso2.uchc.edu

    • Pramod Srivastava

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Glossary

PEPTIDE FINGERPRINT

Unique collection of all peptides generated in a cell or tissue.

ANTIGENIC FINGERPRINT

Unique collection of all the peptides generated in a cell, tumour or virus-infected tissue that are presented to T-cells.

CROSS-PRIMING

An antigen-expressing cell might not directly stimulate the T cells that recognize that antigen. Instead, the antigen must often be transferred from the antigen-expressing cell to a specialized immune cell (most probably a dendritic cell) that then stimulates the cognate naive T cell. Also known as indirect presentation.

NUCLEAR FACTOR-κB

A transcriptional factor that normally resides in the cytosol, but which on stimulation of the cells with certain ligands, translocates to the nucleus where it initiates the transcription of a wide array of immunologically important genes.

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