title: Serial killing of tumor cells by human natural killer cells--enhancement by therapeutic antibodies.
abstract: BACKGROUND
  Natural killer cells are an important component of the innate immune system. Anti-cancer therapies utilizing monoclonal antibodies also rely on the cytotoxicity of NK cells for their effectiveness. Here, we study the dynamics of NK cell cytotoxicity.
  
  
  RESULTS
  We observe that IL-2 activated human NK cells can serially hit multiple targets. Using functional assays, we demonstrate that on an average, a single IL-2 activated NK cell can kill four target cells. Data using live video microscopy suggest that an individual NK cell can make serial contacts with multiple targets and majority of contacts lead to lysis of target cells. Serial killing is associated with a loss of Perforin and Granzyme B content. A large majority of NK cells survive serial killing, and IL-2 can replenish their granular stock and restore the diminished cytotoxicity of 'exhausted' NK cells. IL-2 and IL-15 are equally effective in enhancing the killing frequency of resting NK cells. Significantly, Rituximab, a therapeutic monoclonal antibody increases the killing frequency of both resting and IL-2 activated NK cells.
  
  
  CONCLUSIONS
  Our data suggest that NK cell-based therapies for overcoming tumors rely on their serial killing ability. Therefore, strategies augmenting the killing ability of NK cells can boost the immune system and enhance the effectiveness of monoclonal antibody-based therapies.
authors: Institute for Immunology, University Heidelberg, Heidelberg, Germany.
authors: Rauf
authors: R
authors: Bhat
authors: Carsten
authors: C
authors: Watzl
mesh_terms: D000906:Antibodies / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology; D019002:CD56 Antigen / Q000276:immunology; D016923:Cell Death; D002470:Cell Survival; D005434:Flow Cytometry; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D009369:Neoplasms / Q000276:immunology / Q000473:pathology*
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D019002:CD56 Antigen; D007376:Interleukin-2