Tunable heat shock protein-mediated NK cell responses are orchestrated by STAT1 in Antigen Presenting Cells

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-$$\gamma$$ 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. 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.

PIP-Seq identifies novel heterogeneous lung innate lymphocyte population activation after combustion product exposure

“…Extracellular heat shock proteins can stimulate immune cells and act as an important form of cellular communication in the lung during stress 37 . To broadly assess HSP-related transcripts from multiple lung cell types, we analyzed CD45 + Thy1 - hematopoietic cell and CD45− structural cell responses after BPC exposure (Figure S4 & S5).…”

“…HSC70 is the protein product of Hspa8 and a member of the larger HSP70 family. Hspa8 has been reported to be increased upon exposure to air pollutant 56 and the extracellular form can trigger the activation of immune cells 37 . The increase of Hspa8 was found in almost every lung cell type analyzed in the lung, suggesting that high HSC70 may be present in lungs exposed to BPC.…”

“…Extracellular heat shock proteins can stimulate immune cells and act as an important form of cellular communication in the lung during stress 37 Two of the BPC components, the dioxin TCDD and polyaromatic hydrocarbon BaP have been shown to activate the aryl hydrocarbon receptor (AHR) and lead to oxidative stress 39 . To explore the AHR activity in our model, we assessed the activity distribution of AHR and found greater AHR activity after BPC exposure (Figure 7F).…”

Temperature modulates the osmosensitivity of tilapia prolactin cells

“…At 32°C, however, osmotic responses were abolished or attenuated in a similar manner as observed with prlr2, suggesting that this receptor isoform and stat3 may be linked during the downstream activation of autocrine signaling. Stat1 is activated by heat in mammalian cell models 73,74 , though downstream signaling effects may differ if Stat1 dimerizes or binds with Stat3 75 . Earlier we found stat3 levels to be similar in RPDs of SW-and FW-acclimated tilapia but stat1a levels to be higher in SW sh 29 .…”