Diverse Roles of Heat Shock Proteins in Immune Activation and Tolerance: A Comprehensive Review of Mechanisms and Therapeutic Relevance

Abstract

Heat shock proteins (HSP) are a broad set of proteins that are induced by a variety of cellular stresses. These proteins predominantly act as chaperones of other proteins in the cell. Since inflammation and infection are a source of physio-logic cellular stress, it is unsurprising that the heat shock protein response and the immune response are closely linked. In this chapter, we explore ways in which HSP participate in diverse immune activities, as well as the therapeutic relevance of HSP-immune crosstalk. Firstly, HSP have been found to positively influence the process of immune activation by stimulating innate immune cells and aiding in antigen processing and presentation. Numerous vaccine strategies have been devised based on the finding that HSP can assist in entry of tumor antigens into antigen processing and presentation pathways. These vaccines, which largely consist of HSP-peptide-complexes, have produced striking therapeutic effects in animal tumor models and early clinical studies. In a seeming paradox, HSP have been shown to support immune tolerance and protect against various forms of autoimmunity in mouse models, possibly through the production of IL-10 by regulatory T-cells. These findings have similarly led to efforts to develop HSP-based therapeutic strategies to reduce inflammation associated with arthritis and other inflammatory conditions. We discuss these concepts in detail, and attempt to shed light on why and how HSP influence the immune system to shift towards activation or tolerance.