title: The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells.
abstract: Although natural killer (NK) cells are often described as first line defence against infected or malignant cells which act without the need of prior activation, it is known now that the NK cell activity is tightly regulated by other cells and soluble factors. We show here that the stress-inducible heat shock protein (HSP) 70 activates human NK cells to kill target cells expressing major histocompatibility complex class I chain-related molecule A (MICA) in a natural killer group 2 member D (NKG2D-) dependent manner. The HSP70-derived peptide TKD (TKDNNLLGRFELSG) was able to replace the full-length HSP70 and to exert the same function. Interestingly, the expression of the cytotoxic effector protease granzyme B in NK cells was increased after TKD stimulation. When MICA and MICB expression was induced in human tumour cells by a histone deacetylase inhibitor and NK cells were activated by HSP70 or TKD, both treatments jointly improved the killing of the tumour cells. Thus, the synergistic activity of two stress-inducible immunological danger signals, HSP70 and MICA/B, leads to activation and enhanced cytotoxicity of human NK cells against tumour cells.
authors.affiliation: Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.
authors.forename: Leslie
authors.initials: L
authors.lastname: Elsner
authors.forename: Perris F
authors.initials: PF
authors.lastname: Flügge
authors.forename: Jingky
authors.initials: J
authors.lastname: Lozano
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Muppala
authors.forename: Britta
authors.initials: B
authors.lastname: Eiz-Vesper
authors.forename: Sara Y
authors.initials: SY
authors.lastname: Demiroglu
authors.forename: Dörthe
authors.initials: D
authors.lastname: Malzahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.forename: Edgar
authors.initials: E
authors.lastname: Brunner
authors.forename: Heike
authors.initials: H
authors.lastname: Bickeböller
authors.forename: Gabriele
authors.initials: G
authors.lastname: Multhoff
authors.forename: Lutz
authors.initials: L
authors.lastname: Walter
authors.forename: Ralf
authors.initials: R
authors.lastname: Dressel
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D053804:Granzymes / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012995:Solubility / Q000187:drug effects; D014162:Transfection
chemical_list: D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D051920:NK Cell Lectin-Like Receptor Subfamily D; D010455:Peptides; D053804:Granzymes