Abstract
The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs). This is an important mechanism for cancer immunosurveillance and can also be modeled by vaccination with HSPs through various routes, targeting specific APCs expressing the HSP receptor CD91. Immunological outcomes can be varied as a result of the broad expression of CD91 in different dendritic cell and macrophage populations. We investigated the cellular response of different APCs to the prototypical immunogenic HSP, gp96, in the context of Th1 immunity. Although APCs generally express similar levels of the HSP receptor CD91, we uncovered APC-distinct, downstream signaling pathways activating STAT1, and differential STAT1 induced genes. As a result of this differential and unique signaling we determined that gp96-activated macrophages, but not DCs are capable of activating NK cells to produce IFN-gamma. These data demonstrate that different APC subsets elicit unique intracellular signaling responses to HSPs which result in different patterns of downstream cellular activation and immune responses. Collectively this provides a novel tunable and autochthonous immune response to extracellular HSPs which has important implications on the development of immunity to cancer and infectious disease, as well as homeostasis.
Highlights
The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs)
We have shown that detection of certain extracellular HSPs, including gp[96], hsp[90], hsp[70] and calreticulin, by APCs occurs via the cell surface receptor LRP1/ CD912,3
Using a co-culture system previously characterized by us[15] (Fig. 1C), we tested the ability of peritoneal exudate cells (PECs) and bone marrow derived dendritic cells (BMDCs) to activate NK cells in response to titrated doses of gp[96] (Fig. 1D) and across a wide spectrum of APC densities, up to 4 × 1 06 cells (Fig. 1E)
Summary
The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs). As a result of this differential and unique signaling we determined that gp96activated macrophages, but not DCs are capable of activating NK cells to produce IFN-γ These data demonstrate that different APC subsets elicit unique intracellular signaling responses to HSPs which result in different patterns of downstream cellular activation and immune responses. Gp[96] can engage plasmacytoid DCs (pDCs) to elicit regulatory T cell (Treg) responses that can prevent or revert Th1 mediated (auto)immunity[8,11,12,13] These and other responses to extracellular HSPs are a result of APC-specific signaling and epigenetic modifications within the APC. Inhibition of SHP2 partially restores rapid STAT1 phosphorylation in cDCs to levels similar to macrophages This regulation of signaling networks in different APCs provides a tunable and specific immune response towards a particular insult. Since the release of HSPs can occur in any tissue following cellular aberrancy in response to infection, malignancy or trauma, understanding how diverse tissue-specific APCs respond to extracellular HSPs is important for therapeutic manipulation of immune responses for clinical benefit
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