CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells.
Natural killer (NK) cells play an important role in the immunosurveillance of leukemia. Their reactivity is governed by a balance of activating and inhibitory receptors including various members of the tumor necrosis factor receptor (TNFR) family. Here we report that human NK cells acquire expression of the TNFR family member CD137 upon activation, and NK cells of acute myeloid leukemia (AML) patients display an activated phenotype with substantial CD137 expression. CD137 ligand (CD137L) was detectable on leukemic cells in 35% of 65 investigated AML patients, but not on healthy CD34(+) cells, and expression was associated with monocytic differentiation. Bidirectional signaling following CD137-CD137L interaction induced the release of the immunomodulatory cytokines interleukin-10 and TNF by AML cells and directly diminished granule mobilization, cytotoxicity, and interferon-gamma production of human NK cells, which was restored by blocking CD137. Cocultures of NK cells with CD137L transfectants confirmed that human CD137 inhibits NK-cell reactivity, while activating signals were transduced by its counterpart on NK cells in mice. Our data underline the necessity to study the function of seemingly analog immunoregulatory molecules in mice compared with men and demonstrate that CD137-CD137L interaction enables immune evasion of AML cells by impairing NK-cell tumor surveillance in humans.
Baessler
Tina
T
Department of Hematology/Oncology, Eberhard-Karls University, 72076 Tuebingen, Germany.
Charton
Jean Enno
JE
Schmiedel
Benjamin Joachim
BJ
Grünebach
Frank
F
Krusch
Matthias
M
Wacker
Alexander
A
Rammensee
Hans-Georg
HG
Salih
Helmut Rainer
HR
D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology*; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008875:Middle Aged; D011485:Protein Binding; D015398:Signal Transduction / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D053330:4-1BB Ligand; D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9