The heat-shock protein receptors: some answers and more questions
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Heat-shock protein receptors:
Institution
Heat-shock Protein Receptors:
CD91 (LRP/a2-macroglobulin receptor)
CD91 has been shown to interact directly with gp96 and to mediate
representation of peptides chaperoned by gp96 and other HSPs (22). In
affinity-chromatography experiments, membrane extracts from APCs
were applied to gp96-agarose columns and the bound protei...
R.J. Binder The heat-shock protein receptors: some
R. Vatner
P. Srivastava answers and more questions
Key words: Abstract: The existence of heat-shock protein (HSP) receptors on antigen- Authors’ affiliation:
scavenger receptors; tumour immunity; viral presenting cells (APCs) was hypothesized in 1994. The first such receptor,
R.J. Binder,
immunity CD91 or LRP, was identified and characterized in 2000. The pace of attribution R. Vatner,
has quickened since and during the last three years alone, six putative HSP P. Srivastava
receptors have been identified. These include CD40, LOX-1, CD36, Toll-like 1
Center for Immunotherapy of
receptor-2 (TLR-2), TLR-4 and SR-A. The literature on HSP receptors on APCs Cancer and Infectious
Diseases, University of
is critically examined in this review and future directions are imagined.
Connecticut School of
Medicine, Farmington, CT,
USA
Correspondence to:
Pramod Srivastava
The immunological properties of heat-shock proteins (HSPs) came to University of Connecticut
School of Medicine
light primarily as a result of their ability to elicit anti-tumour immunity MC1601, Farmington
CT 06030-1601
(1, 2). This property, first described for the endoplasmic-reticulum USA
Tel.: þ1 860 679 4444
resident – glucose-regulated HSP gp96 – was subsequently also Fax: þ1 860 679 7905
observed for hsp70 (3), hsp90 (4), calreticulin (5), hsp170 (6) and e-mail: srivastava@nso2.
uchc.edu
hsp110 (6). The antigenic specificity of the HSPs was shown to derive
not from the HSP molecules per se, but from the peptides chaperoned
by them. First suggested in 1989–1991, this idea has been validated
through a large number of structural and immunological studies (see 7,
8 as examples). The mechanism, through which HSPs, or more accur-
ately HSP–peptide complexes, elicit anti-tumour and anti-viral
responses, has been delineated in some detail. The interaction of
HSPs with HSP receptors on antigen-presenting cells (APCs) lies at
the centre of this mechanistic understanding, and is the subject of this
critical review.
HSP–APC interaction has two distinct consequences (Fig. 1):
firstly, the HSP–peptide complexes are taken up by the APCs and
the peptides re-presented on MHC molecules of the APC (9, 10);
secondly, HSPs (regardless of chaperoned peptides) induce the secre-
Received and accepted for publication 28 May 2004 tion of inflammatory cytokines – such as tumour necrosis factor-a
Copyright ß Blackwell Munksgaard 2004 (TNF-a), interleukin-1b (IL-1b), IL-12, IL-6 and GM-CSF – by macro-
doi: 10.1111/j.1399-0039.2004.00299.x
phages and dendritic cells (DCs) (11–16), chemokines – such as MCP-1,
Tissue Antigens 2004: 64: 442–451
Printed in Denmark. All rights reserved MIP-1 and RANTES – by macrophages (17, 18), nitric oxide (NO)
442
, Binder et al : Heat-shock protein receptors
Fig. 1. The interaction of heat-shock proteins (HSPs) with receptors on antigen-presenting cells (APCs) leads to two outcomes. In the
specific or adaptive outcome, HSP-chaperoned peptides are internalized by endocytosing receptors and the peptides are processed and presented on MHC
molecules of the APC. In the innate or peptide-non-specific outcomes, HSPs engage signalling receptors that trigger NF-kb activation. The APCs release
cytokines, chemokines and nitric oxide (NO) and upregulate the expression of co-stimulatory molecules and MHC-II.
Tissue Antigens 2004: 64: 442–451 443
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