All for CD91 and CD91 for all

Justin Stebbing1,*, Philip Savage2, Steve Patterson1 and Brian Gazzard1

1 Department of Immunology, Division of Investigative Science, Faculty of Medicine, Imperial College of Science, Technology and Medicine, The Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK; 2 Department of Oncology, Velindre Hospital, Cardiff, Wales, UK


    Abstract
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 Abstract
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Heat shock proteins interact with antigen-presenting cells through their receptor, CD91, eliciting a cascade of events including maturation, activation and representation of chaperoned foreign peptides with class I molecules on their surface. In turn, this facilitates recognition of non-self leading to induction of a cytotoxic T cell response. The abundance of heat shock proteins in tumours and their presence in virion coats makes them attractive propositions for use in antitumour and antiviral strategies.

Keywords: heat shock proteins, HIV, cancer, receptors

A current UK advertising campaign contends (with irony) that ‘Apparently there are more important things in life than fashion. Yeah, right.’ (www.frenchconnection.com). It is safe to argue that new therapeutic strategies that are designed to modulate the course of retroviral infection in nearly 60 million HIV-1-infected individuals worldwide fit this paradigm.1 Although novelty is clearly the key component of fashion for some, the story of heat shock proteins (HSPs) begins ~40 years ago, when the temperature on an incubator full of fruit flies was inadvertently turned up to 60°C.2,3 Under light microscopy, the salivary gland chromosomes of the fruit flies, thus ‘heat-shocked’, showed dilated puffs indicative of transcriptional activity at discrete loci. These loci are now known to encode HSPs, which have since been identified in all species, expressed in all cells and in a wide variety of intracellular locations.4

Organisms—from bacteria to humans—respond to high temperatures by inducing the synthesis of HSPs and decreasing the production of other proteins. The synthesis of HSPs is not only induced by heat but also by other stressors such as oxidation, pH change, carbon monoxide, nicotine, H2O2, benzene, teratogens, dust, UV light and other carcinogens found in the environment. HSPs are the oldest known proteins, remarkably conserved between species and constitute the single most abundant group of proteins inside cells. Like the cyclophilins (which, incidentally, act as a cytoplasmic assembly focus for HIV capsid proteins), HSPs form a family of intracellular chaperones that facilitate protein folding and assembly, and act as buffers to stochastic and potentially destabilizing environmental forces. In doing so, HSPs protect proteins from stress.5,6

There are four ‘fashionable’ characteristics of HSPs that lend credence to their use in antitumour and antiviral strategies:

1. HSPs bind and release peptides in an energy-dependent process requiring ATP. Such binding has been referred to as promiscuous, as it covers such a broad range of foreign material, including viral peptides and tumour antigens.

2. HSP–peptide complexes derived from virus-infected cells (or tumours) are capable of binding to antigen-presenting cells, with subsequent internalization and cross-presentation onto major histocompatibility complex (MHC) class I molecules.

3. Engagement of HSP–peptide complexes with antigen-presenting cells leads to expression of co-stimulatory molecules, maturation and cytokine release. Activated antigen-presenting cells, such as dendritic cells, then present the previously bound peptides efficiently and activate specific CD8+ T cells, independent of CD4 T cell help.

4. In transferring or ‘cross-presenting’ antigenic peptides from outside the cell onto the ‘endogenous’ class I pathway, they are capable of eliciting cellular CD8+ cytotoxic T cell-mediated immunity.

A large number of HSPs have been identified, and their names provide reference to their intracellular location and/or molecular weight. The idea of an HSP receptor was at first considered something of an aberration: receptors were considered to be suited exclusively to the detection of secreted molecules such as hormones or cytokines, not intracellular molecules. However, uptake of antibody-bound fragments was shown to occur through Fc receptors,7 and the existence of an HSP receptor was subsequently hypothesized to explain the ability of HSP–peptide complexes to pulse antigen-presenting cells, leading to a cytotoxic T cell response.815

CD91 had been identified previously as a receptor for the serum protein {alpha}-2-macroglobulin, a ‘natural’ protease inhibitor that—like HSPs—is found across many species.16 Pathogens often utilize their own proteases in establishing successful infection. {alpha}-2-Macroglobulin is able to bind these pathogens by acting first as a substrate for pathogenic proteases and then trapping them, in an altered conformation, prior to endocytosis through CD91. The foreign protease is then digested into amino acids, acting as a source of host nourishment. However, as the ‘molecular arms race’ between hosts and pathogens has progressed over evolutionary epochs, pathogens have acquired ever more fashionable and sophisticated means to evade host responses.17

In turn, hosts have developed the means to overcome such subversion strategies. In this scenario, viruses or other pathogens infect cells, and then replicate and destroy the host cell, but the HSPs contained therein transfer information (the foreign peptides) regarding the infected environment to CD91. This large cell surface dimer, along with the HSPs, is internalized and whereas a proportion of it enters an acidic compartment for digestion (once again providing nutrition for the host), the remainder enters a neutral pH compartment that funnels peptides into the classical class I presenting pathway. The MHCs bind and present them to CD8+ T cells. On recognizing non-self, such T cells are induced. They clonally proliferate and mediate (perforin is secreted) killing, prior to apoptosis of many of these effectors and subsequent persistence of long-lived memory cells.18

CD91 was first identified by Binder et al.19 as the receptor for gp96, and then by Basu et al.20 as a common receptor for other HSPs such as HSP70, HSP90 and calreticulin. Srivastava et al.4 and his colleagues21 have made the interesting observation that CD91 appears to be a common receptor for all other identified HSPs, and that blocking of CD91 with antibodies completely inhibits the phenomenon of re-presentation of peptides that are carried or chaperoned by HSPs. This includes the immunogenicity conferred by the abundant HSPs that are found in tumour lysates.22 Others have shown previously that HSP preparations can elicit cytotoxic T lymphocyte (CTL) responses between mice of different MHC types, and it appears that CD91 is a key portal for indirect presentation of foreign antigen.9 As HSPs are essential for life, HSP ‘knockout’ organisms are non-viable and this abrogates the use of this elegant methodology to elucidate their function further. However, by using the putative chemotherapeutic agents radicicol and geldanamycin, pharmacological blockade of the ATPase function of HSPs has yielded results similar to antibody blockade.6,21

CD91 has been demonstrated recently to bind and internalize {alpha}-defensins in a saturable and dose-dependent manner.23 These small molecules are secreted from stimulated CD8+ T cells in the rare minority of individuals who are infected with HIV-1 for more than 10 years with no evidence of progressive disease, whereas remaining off treatment (termed long-term non-progressors).24 Expression of CD91 is increased in such individuals, whereas differences between non-progressors and other patients (in their expression of a large range of dendritic cell activation and maturation markers) remain insignificant, both before and after antigenic challenge.25 The finding that gp96 stimulates perforin release26 and that perforin levels are maintained at high levels in long-term non-progressors,27 affords CD91 the position at the centre of a unifying hypothesis in these individuals.

HSPs, which have now been found within virion coats,28 appear to be an integral part of the viral life cycle.29 The addition of HIV-1 to monocytes reduces measured CD91 expression, confirming its role not only as an HSP receptor but also as a receptor able to bind virion-associated HSPs.25 It appears quite conceivable that within the context of host–pathogen evolution, HSPs have co-opted ancient viral replicative strategies to stimulate aspects of innate and adaptive immunity. This is turn would act to prevent overwhelming infection in the context of excessive replication, preserving the host and ultimately the pathogen. It will be interesting to observe whether those invaders that cause rapid and overwhelming infection (e.g. haemorrhagic fever viruses) lack such strategies to stimulate host responses, thus mitigating aspects of their own preservation.

The potential to push the balance between sustained infection and host immune control towards the latter has not gone unnoticed. In the treatment of cancer, randomized trials are underway using renal tumour-derived autologous HSPs. In a published, randomized melanoma study using HSPs derived from patients’ own tumour samples, complete responses were observed in a minority of patients.30 In other studies, the oncogenic human papillomavirus proteins E6 and E7 have been fused to HSP65, and clinical trials will commence to investigate regression of cervical dysplasia. The immunological data are already convincing, although it remains to be seen whether this correlates with sustained clinical responses. It is increasingly clear that CD91, termed the ‘common heat shock protein receptor’ represents an important route for stimulating a CD8+ T cell response by MHC class I-restricted presentation. This may also be a fairly general mechanism by which the innate immune system can stimulate the adaptive arm in viral infections and tumours. Up-regulation of CD91 may therefore represent a useful therapeutic and perhaps preventative antiviral or antitumour strategy.


    Footnotes
 
* Corresponding author. Tel: +44-208-746-8251; Fax: +44-208-746-5997; E-mail: j.stebbing{at}imperial.ac.uk Back


    References
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