Interaction of Toll-Like Receptors with the Molecular Chaperone Gp96 Is Essential for Its Activation of Cytotoxic T Lymphocyte Response

Abstract

The heat shock protein gp96 elicits specific T cell responses to its chaperoned peptides against cancer and infectious diseases in both rodent models and clinical trials. Although gp96-induced innate immunity, via a subset of Toll like receptors (TLRs), and adaptive immunity, through antigen presentation, are both believed to be important for priming potent T cell responses, direct evidence for the role of gp96-mediated TLR activation related to its functional T cell activation is lacking. Here, we report that gp96 containing mutations in its TLR-binding domain failed to activate macrophages, but peptide presentation was unaffected. Moreover, we found that peptide-specific T cell responses, as well as antitumor T cell immunity induced by gp96, are severely impaired when the TLR-binding domain is mutated. These data demonstrate the essential role of the gp96-TLR interaction in priming T cell immunity and provide further molecular basis for the coupling of gp96-mediated innate with adaptive immunity.

Myeloid Endoplasmic Reticulum Resident Chaperone GP96 Facilitates Inflammation and Steatosis in Alcohol‐Associated Liver Disease

“…Our findings on the pathophysiological significance of macrophage GP96 adds to our understanding of the mechanisms associated with ALD and have implications in developing therapeutics. In fact, mutations in GP96 can reduce macrophage activation while retaining antigen presentation activity ( 49 ) to combat infections in ALD. Although complete inhibition of liver macrophage activation and inflammatory responses in ALD can be a clinical limitation, targets that promote recovery/restorative phenotype to facilitate elimination of damaging triggers in the liver could be beneficial.…”

Shotgun Proteomics of Human Dentin with Different Prefractionation Methods

“…Furthermore, the detected endoplasmin (a.k.a. gp96) has been shown to activate the TLR2/4 pathway on regulatory T-cells via a C-terminal loop structure 27 , 28 and might function as ligand for toll-like receptors in dental pulp 29 .…”

Extracellular gp96 is a crucial mediator for driving immune hyperactivation and liver damage

“…Meanwhile, extracellular gp96-peptide complexes may be taken up by antigen presenting cells (APCs), and the associated peptides can be cross-presented to MHC I molecules for CD8 + T cell activation 19 . Second, gp96 itself can prime and activate multiple immune cells and induce the secretion of inflammatory cytokines by interacting with its receptors CD91, toll like receptor(TLR)2/4 and promoting the downstream NF-κB pathway, or activating NLRP3 inflammasomes of antigen presenting cells (APCs) 13,[20][21][22] . Recently, several lines of evidence indicate that aberrantly elevated levels of extracellular gp96 are associated with chronic inflammation and autoimmune diseases.…”