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.
Highlights
IntroductionAs a member of the heat shock protein 90 (HSP90) family, gp (glucose-regulated protein 94, GRP94) is one of the most abundant chaperones in the endoplasmic reticulum (ER)
As a member of the heat shock protein 90 (HSP90) family, gp96 is one of the most abundant chaperones in the endoplasmic reticulum (ER)
A previous study demonstrates that the GWXGNMER motif within the client-binding domain (CBD, aa 652–678) of gp96 is essential for its interaction with Toll like receptors (TLRs) [10]
Summary
As a member of the heat shock protein 90 (HSP90) family, gp (glucose-regulated protein 94, GRP94) is one of the most abundant chaperones in the endoplasmic reticulum (ER). Both rodent models and clinical trials have demonstrated that gp purified from tumors or complexed with viral antigens in vitro elicits antitumor effects or antigen-specific humoral and CD8+ T cell (CTL) immunity against tumors and viruses [1,2,3]. Gp96 and TLRs Interaction Is Essential for CTL Activation in study design, data collection and analysis, decision to publish, or preparation of the manuscript Together with HSP70 and HSP90 in the cytosol, gp, TAP (transporter associated with antigen processing) molecules, and calreticulin in the ER are thought to constitute a relay line for antigenic peptide transfer from the cytosol to MHC class I molecules in a concerted
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