Requirements for control of B-cell lymphoma by NK cells

Eur J Immunol. 2010 Feb;40(2):494-504. doi: 10.1002/eji.200939937.


The role of NK cells in the control of endogenously arising tumors is still unclear. We monitored activation and effector functions of NK cells in a c-myc-transgenic mouse model of spontaneously arising lymphoma. At early stages, tumors demonstrated reduced MHC class I expression and increased expression of natural killer group 2D ligands (NKG2D-L). NK cells in these tumors showed an activated phenotype that correlated with the loss of tumor MHC class I. With increasing tumor load however, NK-cell effector functions became progressively paralyzed or exhausted. In later stages of disease, tumors re-expressed MHC class I and lost NKG2D-L, suggesting a role of these two signals for NK cell-mediated tumor control. Testing a panel of lymphoma cell lines expressing various MHC class I and NKG2D-L levels suggested that NK cell-dependent tumor control required a priming and a triggering signal that were provided by MHC class I down-regulation and by NKG2D-L, respectively. Deleting either of the "two signals" resulted in tumor escape. At early disease stages, immune stimulation through TLR-ligands in vivo efficiently delayed lymphoma growth in a strictly NK cell-dependent manner. Thus, NK-receptor coengagement is crucial for NK-cell functions in vivo and especially for NK cell-mediated tumor surveillance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic / immunology*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic
  • Genes, myc / genetics
  • H-2 Antigens / immunology
  • H-2 Antigens / metabolism
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leukocyte Common Antigens / immunology
  • Leukocyte Common Antigens / metabolism
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / immunology*
  • Lymphoma, B-Cell / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NK Cell Lectin-Like Receptor Subfamily K / immunology
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / immunology
  • Tumor Escape / immunology


  • H-2 Antigens
  • Klrk1 protein, mouse
  • NK Cell Lectin-Like Receptor Subfamily K
  • Interferon-gamma
  • Leukocyte Common Antigens