The endogenous danger signals HSP70 and MICA cooperate in the activation of cytotoxic effector functions of NK cells |
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| Authors: | Leslie Elsner Perris F Flügge Jingky Lozano Vijayakumar Muppala Britta Eiz‐Vesper Sara Y Demiroglu Dörthe Malzahn Thomas Herrmann Edgar Brunner Heike Bickeböller Gabriele Multhoff Lutz Walter Ralf Dressel |
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| Institution: | 1. Department of Cellular and Molecular Immunology, University of G?ttingen, Germany;2. Department of Immunogenetics, University of G?ttingen, Germany;3. Department of Genetic Epidemiology, University of G?ttingen, Germany;4. Institute for Transfusion Medicine, Hannover Medical School, Germany;5. Institute of Virology and Immunobiology, University of Würzburg, Germany;6. Department of Medical Statistics, University of G?ttingen, Germany;7. Department of Radiotherapy and Radiooncology, Technische Universit?t München and Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Germany;8. Department of Primate Genetics, German Primate Center, Germany |
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| 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. |
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| Keywords: | heat shock protein 70 NKG2D ligands natural killer cells cellular cytotoxicity cancer immunotherapy |
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