Heat Shock Proteins are Targets for T Cell Regulation: How Microbial HSP Induce IL10 Producing Anti-Inflammatory T Cells

Abstract

Mechanisms of anti-inflammatory T cell regulation are studied very actively, especially since the (re-)discovery of T cell subpopulations with specialized regulatory activities. This is expected to lead to the development of novel immunotherapeutic approaches, especially in chronic autoimmune diseases. HSP are possible targets for regulatory T cells due to their enhanced expression in inflamed (stressed) tissues and the collected evidence that HSP immunizations induced anti-inflammatory immunoregulatory T cell responses. First evidence for an immuno-regulatory role of heat shock proteins (HSP) in autoimmunity was obtained through the analysis of T cell responses in the rat model of adjuvant arthritis and the findings that HSP immunizations protected against the induction of various forms of autoimmune arthritis in rat and mouse models. Since then, immune reactivity to HSP was found to result from inflammation in various disease models and in a variety of human inflammatory conditions. Now, also in the light of a growing interest in T cell regulation, it is of interest to further explore the mechanisms through which HSP have the potential to trigger immune regulatory pathways, capable of suppressing inflammatory diseases. And this even more, since in initial clinical trials in patients with RA and type 1 diabetes, HSP-derived peptides have been seen to promote the production of anti-inflammatory cytokines. In addition, the growing concern over the rise of some autoimmune conditions and allergies in Western countries, possibly related to changed life style, has generated interest in immune responsiveness to particular microbial antigens, such as HSP, which are known to be dominantly immunogenic and to have a disease preventive/therapeutic effect in models of autoimmune diseases and allergic asthma. Heat shock proteins have received attention by immunologists since their discovery and especially since it was observed that under various conditions immune responses to HSP were readily developing. Through their evolutionary conservation, their role in maintaining integrity of cellular proteins and their stress inducibility, their potential impact on the organization of immune reactivity in mammals is considered to be broad and multifacetted. Their role as chaperones for intracellular proteins such as tumor antigens, their role as proteins to deliver protein antigens for cross-presentation to CD8+ T cells and some other aspects have been the subject of various reviews (Morimoto, 1998; Nicchitta, 2003). The current chapter will concentrate on immune responses induced by HSP as antigens, and the potential of such responses to control inflammation