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CD137 ligand mediates opposite effects in human and mouse NK cells and impairs NK-cell reactivity against human acute myeloid leukemia cells.
- Source :
-
Blood [Blood] 2010 Apr 15; Vol. 115 (15), pp. 3058-69. Date of Electronic Publication: 2009 Dec 14. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- 4-1BB Ligand genetics
Aged
Aged, 80 and over
Animals
Cell Line, Tumor
Cytokines metabolism
Female
Gene Expression Regulation, Leukemic
Histocompatibility Antigens Class I immunology
Humans
Immune Tolerance immunology
Killer Cells, Natural pathology
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute pathology
Lymphocyte Activation immunology
Male
Mice
Middle Aged
Protein Binding
Signal Transduction immunology
Tumor Necrosis Factor Receptor Superfamily, Member 9 metabolism
Up-Regulation genetics
4-1BB Ligand immunology
Killer Cells, Natural immunology
Leukemia, Myeloid, Acute immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 115
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 20008791
- Full Text :
- https://doi.org/10.1182/blood-2009-06-227934