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

• Published in: PloS one 2016-05, Vol.11 (5), p.e0155202-e0155202
• Main Authors: Liu, Weiwei, Chen, Mi, Li, Xinghui, Zhao, Bao, Hou, Junwei, Zheng, Huaguo, Qiu, Lipeng, Li, Zihai, Meng, Songdong
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Amino Acid Sequence; Analysis; Animal models; Animals; Antigen presentation; Antigen Presentation - immunology; Antigens; Binding; Binding sites; Biology and Life Sciences; Cancer; Cell activation; Cell Line; Clinical trials; Coupling (molecular); Cross-Priming - immunology; Cytokines - metabolism; Cytotoxicity; Endoplasmic reticulum; Epitopes, T-Lymphocyte - chemistry; Epitopes, T-Lymphocyte - immunology; Female; Glycoprotein gp96; Heat shock proteins; Humans; Immune system; Immunity; Immunoglobulins; Immunology; Infectious diseases; Innate immunity; Laboratory animals; Lymphocyte Activation - immunology; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; Medical research; Medicine and Health Sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - pathology; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mutation; Penicillin; Peptides; Peptides - chemistry; Peptides - immunology; Priming; Protein Binding; Protein Interaction Domains and Motifs; Receptors; Research and Analysis Methods; T cells; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Toll-like receptors; Toll-Like Receptors - chemistry; Toll-Like Receptors - metabolism; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0155202

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.