Role of chaperones and FcγR in immunogenic death

Abstract

Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

Heat Shock Protein 25-Enriched Plasma Transfusion Preconditions the Heart against Doxorubicin-Induced Dilated Cardiomyopathy in Mice

“…Thus, it is not clear whether this increase in Hsp27 in the failing human heart (Hsp25 in murine heart) is the result of an unsuccessful protective mechanism or whether the increased expression of Hsp25 indeed potentiates the loss of cardiomyocytes in the heart. Extracellular Hsps (eHsps), which are present in blood plasma, are being actively studied for their role in innate immunity (Multhoff, 2006;Schmitt et al, 2007;Dhodapkar et al, 2008). Dox has been reported to activate monocytes and macrophages in the circulation and induce an immunogenic response through activation of interleukin-1 family receptors such as Toll-like receptors (TLRs) (Riad et al, 2008).…”

Immunotherapy of head and neck cancer using tumor antigen-specific monoclonal antibodies

“…In human cells, there are three activating FcγRs-FcγRI, FcγRIIa, and FcγRIII-and one inhibiting FcγR-FcγRIIB [39]with FcγRIIa being the dominant receptor on APCs. In a murine model, ovalbumin and anti-ovalbumin immune complexes given to DCs were able to generate ovalbuminspecifi c T-cell responses.…”

Introduction: the immune response against dying cells

“…Importantly, one single molecular entity that is exposed or released by dying tumor cells might act on multiple PRRs, as this has been suggested for HMGB1, which may act on the receptor for advanced glycated endproducts (RAGEs) as well as toll receptor, toll-like receptors including TLR2 and TLR4 [7]. Similarly, HSPs exposed or released by tumor cells may act on multiple receptors including CD91, scavenger receptor, TLR2 and TLR4, among others [6]. Polynucleotides and oligonucleotides derived from degrading DNA or RNA can act on TLR3, TLR7, TLR8, or TLR9 as well as on intracellular receptors including RIG1, MDA5, or LGP2, while ATP and its degradation products may activate or inhibit distinct classes of purinergic receptors [8].…”

“…Neutralization of MFG-E8 may enhance inflammatory response and promote anticancer immune responses [11]. In the case of opsonizing antibodies (which often kill the target cell), the interaction between the antibody and Fcg receptors (which may be either activation or inhibitor Fcg receptors) has a major effect on DC function [6].…”

“…The multiple dents of the key are composed by defined molecular entities including proteins that appear at the surface of stressed and dying cells (such as calreticulin and heat shock proteins, HSPs), lipid moieties that flip from the inner plasma membrane leaflet to the outer leaflet (such as phosphatidylserine) [6], proteins that are released into the supernatant of cells (such as HMGB1) [7] as well as nucleic acids and their degradation products (oligonucleotides, nucleotides, and nucleosides) that appear in the extracellular space [8]. The molecular mechanism accounting for the exposure or release of immunogenic signals is presently under intense investigation.…”