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.

• Authors: Weiwei Liu, Mi Chen, Xinghui Li, Bao Zhao, Junwei Hou, Huaguo Zheng, Lipeng Qiu, Zihai Li, Songdong Meng
• Journal: PloS one (PLoS One) Vol. 11 Issue 5 Pg. e0155202 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 27183126 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Epitopes, T-Lymphocyte
• Membrane Glycoproteins
• Peptides
• Toll-Like Receptors
• endoplasmin

Topics

• Amino Acid Sequence
• Animals
• Antigen Presentation (immunology)
• Cell Line
• Cross-Priming (immunology)
• Cytokines (metabolism)
• Epitopes, T-Lymphocyte (chemistry, immunology)
• Female
• Humans
• Lymphocyte Activation (immunology)
• Macrophages (immunology, metabolism)
• Melanoma, Experimental (immunology, metabolism, pathology)
• Membrane Glycoproteins (genetics, metabolism)
• Mice
• Mutation
• Peptides (chemistry, immunology)
• Protein Binding
• Protein Interaction Domains and Motifs
• T-Lymphocytes, Cytotoxic (immunology, metabolism)
• Toll-Like Receptors (chemistry, metabolism)