Heat shock protein 70: role in antigen presentation and immune stimulation

Abstract

Heat shock proteins (HSP) when released into the extracellular milieu can act simultaneously as a source of antigen due to their ability to chaperone peptides and as a maturation signal for dendritic cells, thereby inducing DCs to cross-present antigens to CD8+ T-cells. HSP can also act independently from associated peptides, stimulating the innate immune system. Previous results regarding the activation of NK cells by HSP70 cell surface expression on tumour cells and soluble HSP70 will be further covered elsewhere within this issue. For cross-presentation, HSP70-peptide complexes (HSP70-PC) were used from two human melanoma cell lines that differ in the expression of the tumour-associated antigen tyrosinase. Purified HSP70-PC consists of both the constitutively expressed HSC70 and the inducible HSP70. HSP70-peptide complexes purified from tyrosinase positive (HSP70-PC/tyr+) human melanoma cells, incubated with immature DCs, results in the activation of HLA-*A0201-restricted tyrosinase peptide-specific T-cells. Receptor-mediated uptake of HSP70-PC by DCs and intracellular transport are required for efficient MHC class I restricted cross-presentation of chaperoned peptides. Demonstration of HSP70-PC mediated cross-presentation of such non-mutated naturally expressed tumour antigens is of special clinical interest with regard to hyperthermia. Tumour regression and improved local control have been shown within clinical phase II/III trials integrating regional hyperthermia combined with radiation and/or chemotherapy in multimodal treatment strategies. According to the proposed concept, local necrosis induced by hyperthermic treatment induces the release of HSPs, followed by uptake, processing and presentation of associated peptides by DCs. By acting as chaperone and a signal for DC maturation, HSP70-PC might efficiently prime circulating T-cells. Therefore, upregulating HSP70 and causing local necrosis in tumour tissue by hyperthermia offers great potential as a new approach to directly activate the immune system.

Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms

“…By using ATP, and working in concert with other chaperones and co-chaperones, the members of the Hsp70-family take part in nearly all of the typical intracellular chaperone functions, including protein folding [21,22,30,38], refolding of damaged proteins [68], inhibition of aggregation [30,38], resolubilization of aggregated proteins [73], the transport of several proteins [30,38], and the control of several signal transduction pathways [9,60], including the induction of senescence [24]. Furthermore, Hsp70 proteins are also involved in many processes outside the cell, including cytoprotection [36,37,41], cytokine-releasing effects, and the modulation of various immune functions [39,51,53,54,64,65,72,76,84].…”

“…Extracellular Hsp70 also induces inducible nitric oxide (NO) synthase and NO release from macrophages [61]. Uncomplexed Hsp70 may also activate NK lymphocytes (NK cells) [51,53]. Although other authors could not detect these effect with highly purified Hsp70 preparations, and expected an endotoxin contamination as a reason behind such effects [7,84], new results confirmed the real effect of uncomplexed extracellular Hsp70 as a danger signal inducing the secretion of proinflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6) from monocytes and macrophages [1,16].…”

“…Because of its chaperoning ability, uncomplexed Hsp70 binds other peptides, and as a complex induces receptor-mediated uptake into antigen-presenting cells (i.e. macrophages, dendritic cells) to cross-present this complex as an antigen (coupled with MHC-I or MHC-II molecules) to cytotoxic T cells and NK cells [8,10,51,74,75,79]. Although bacterial Hsp70 associates mainly with bacterial antigens, human Hsp70 associates peptides such as self peptides, tumor peptides, or viral peptides because these are derived from proteins synthesized in human cells [75].…”

“…Although bacterial Hsp70 associates mainly with bacterial antigens, human Hsp70 associates peptides such as self peptides, tumor peptides, or viral peptides because these are derived from proteins synthesized in human cells [75]. This means that the antigenpresenting function of Hsp70 is important not only against bacteria, but also as an initiator of immune defense against tumor cells and viral infections [8,10,51,71,74,77,79].…”

“…There is increasing evidence for functions of Hsp70 outside of the cell, such as cytoprotection [36,37,41] and modulation of cytokine release and immunity [39,51,53,54,58,63,65,72,76,84]. All these functions may be important in relation to salivary Hsp70.…”