Requirements for control of B-cell lymphoma by NK cells.
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.
Brenner
Christoph D
CD
Helmholtz-Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Institut für Molekulare Immunologie, München, Germany.
King
Susan
S
Przewoznik
Margarethe
M
Wolters
Imke
I
Adam
Christian
C
Bornkamm
Georg W
GW
Busch
Dirk H
DH
Röcken
Martin
M
Mocikat
Ralph
R
D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D006183:H-2 Antigens / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019139:Tumor Escape / Q000276:immunology
D006183:H-2 Antigens; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens