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  • Review Article
  • Published:

Heat-shock proteins induce T-cell regulation of chronic inflammation

Nature Reviews Immunology volume 5, pages 318–330 (2005)Cite this article

Key Points

  • Heat-shock proteins (HSPs) are highly immunogenic, despite there being a high level of sequence conservation between bacteria and mammals.

  • Intrinsic features of HSPs seem to endow them with an ability to induce T-cell regulation during chronic inflammation.

  • In particular, HSP60 and HSP70 have been shown to effectively induce immunoregulation and suppress disease in experimental models of inflammatory disease and in early-stage clinical trials.

  • In animal models, immunization with microbial HSPs leads to the production of T cells that crossreact with self-HSPs. Such self-HSP-specific T cells produce regulatory cytokines, such as interleukin-10, and have disease-suppressive potential.

  • Immune responses to HSPs develop in chronic inflammatory diseases, such as rheumatoid arthritis, type 1 diabetes and atherosclerosis.

  • T-cell responses to human HSP60 in patients with juvenile idiopathic arthritis are associated with a benign course of disease and the induction of disease remission.

  • In clinical trials for the treatment of type 1 diabetes and rheumatoid arthritis, HSP-derived peptides have been shown to promote a switch from a pro-inflammatory cytokine-secretion profile of T cells to a regulatory cytokine-secretion profile.

  • Through triggering receptors of the innate immune system and the subsequent production of regulatory cytokines, HSPs might 'set the scene' for the development of regulatory adaptive immune responses.

Abstract

Immune responses to certain heat-shock proteins (HSPs) develop in almost all inflammatory diseases; however, the significance of such responses is only now becoming clear. In experimental disease models, HSPs can prevent or arrest inflammatory damage, and in initial clinical trials in patients with chronic inflammatory disease, HSP-derived peptides have been shown to promote the production of anti-inflammatory cytokines, indicating that HSPs have immunoregulatory potential. In this Review, we discuss the unique characteristics of HSPs that endow them with these immunoregulatory qualities.

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Figure 1: Cellular interactions that induce a regulatory mode in heat-shock-protein-specific T cells.
Figure 2: Regulation through self-heat-shock-protein-specific T cells.
Figure 3: Triggering factors in heat-shock-protein-directed immunoregulation.

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Acknowledgements

We thank A. Beijer for help with the manuscript. This work was funded, in part, by the European Commission project entitled HSP for Therapy: HSP60 as a novel therapeutic target for diabetes and RA.

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Authors and Affiliations

  1. Division of Immunology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, Utrecht, 3584CL, The Netherlands

    Willem van Eden, Ruurd van der Zee & Berent Prakken

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  1. Willem van Eden
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  2. Ruurd van der Zee
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  3. Berent Prakken
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Correspondence to Willem van Eden.

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DATABASES

Entrez Gene

human HSP60

IL-10

M. tuberculosis HSP60

TGF-β

FURTHER INFORMATION

HSP for Therapy

Utrecht University Faculty of Veterinary Medicine, Division of Immunology

Glossary

MOLECULAR CHAPERONES

Proteins that interact with unfolded or partially folded protein subunits and facilitate correct folding.

ADJUVANT-INDUCED ARTHRITIS

An experimental animal model of arthritis in which disease is induced by the administration of heat-killed mycobacteria in oil.

CENTRAL TOLERANCE

Tolerance created at the level of the central lymphoid organs. For T cells, positive and negative selection occurs in the thymus.

TRANSLOCATION

The energy-dependent active transport of proteins through cellular or subcellular membranes.

DERMATOMYOSITIS

One of a group of acquired muscle diseases that are known as inflammatory myopathies.

JUVENILE IDIOPATHIC ARTHRITIS

(JIA). The most common rheumatic disease of childhood. It is characterized by local inflammation in the joints, which leads to joint destruction.

PROTEOGLYCAN-INDUCED ARTHRITIS

An experimental animal model of chronic, relapsing arthritis. Disease is induced by immunization with the human proteoglycan aggrecan.

MUCOSAL TOLERANCE

Peripheral tolerance that is produced by exposure to antigen at mucosal surfaces.

ALTERED-PEPTIDE LIGAND

A peptide that has high homology with the sequence of an agonist peptide and induces only a partial response by T cells specific for the agonist peptide.

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van Eden, W., van der Zee, R. & Prakken, B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5, 318–330 (2005). https://doi.org/10.1038/nri1593

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