The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells.
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.
Elsner
Leslie
L
Department of Cellular and Molecular Immunology, University of Göttingen, Göttingen, Germany.
Flügge
Perris F
PF
Lozano
Jingky
J
Muppala
Vijayakumar
V
Eiz-Vesper
Britta
B
Demiroglu
Sara Y
SY
Malzahn
Dörthe
D
Herrmann
Thomas
T
Brunner
Edgar
E
Bickeböller
Heike
H
Multhoff
Gabriele
G
Walter
Lutz
L
Dressel
Ralf
R
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
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