title: 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.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Mi
authors.initials: M
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Xinghui
authors.initials: X
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Bao
authors.initials: B
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Junwei
authors.initials: J
authors.lastname: Hou
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Huaguo
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Institute of Life Sciences, Jiangsu University, Zhenjiang, P.R. China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States of America.
authors.forename: Zihai
authors.initials: Z
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, P.R. China.
authors.forename: Songdong
authors.initials: S
authors.lastname: Meng
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D002460:Cell Line; D045142:Cross-Priming / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D010455:Peptides; D051193:Toll-Like Receptors; C053387:endoplasmin