Back to Search
Start Over
A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia.
- Source :
-
Blood [Blood] 2009 Apr 02; Vol. 113 (14), pp. 3226-34. Date of Electronic Publication: 2008 Dec 15. - Publication Year :
- 2009
-
Abstract
- Large granular lymphocyte (LGL) leukemia, or LGLL, is characterized by increased numbers of circulating clonal LGL cells in association with neutropenia, anemia, rheumatoid arthritis, and pulmonary artery hypertension (PAH). Emerging evidence suggests that LGLL cells with a CD8(+)CD28(null) phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared with CD8(+)CD28(null) T cells from healthy controls, CD8(+)CD28(null) T cells from LGLL patients have acquired the ability to directly lyse pulmonary artery endothelial cells and human synovial cells. Here, we show that LGLL cells from patients possess enhanced cytotoxic characteristics and express elevated levels of activating natural killer receptors as well as their signaling partners, DAP10 and DAP12. Moreover, downstream targets of DAP10 and DAP12 are constitutively activated in LGLL cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. These are the first results to show that activating NKR-ligand interactions play a critical role in initiating the DAP10 and DAP12 signaling events that lead to enhanced lytic potential of LGLL cells. Results shown suggest that inhibitors of DAP10 and DAP12 or other proteins involved in this signaling pathway will be attractive therapeutic targets for the treatment of LGLL and other autoimmune diseases and syndromes.
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing metabolism
CD28 Antigens metabolism
CD8-Positive T-Lymphocytes metabolism
CD8-Positive T-Lymphocytes pathology
Endothelial Cells immunology
Endothelial Cells pathology
Extracellular Signal-Regulated MAP Kinases metabolism
Humans
K562 Cells
Leukemia, Large Granular Lymphocytic genetics
Leukemia, Large Granular Lymphocytic metabolism
Leukemia, Large Granular Lymphocytic pathology
Membrane Proteins genetics
Membrane Proteins metabolism
Phosphatidylinositol 3-Kinases metabolism
Pulmonary Artery immunology
Pulmonary Artery pathology
Receptors, Immunologic genetics
Receptors, Immunologic metabolism
Receptors, Natural Killer Cell metabolism
Signal Transduction genetics
Tumor Cells, Cultured
Adaptor Proteins, Signal Transducing physiology
CD8-Positive T-Lymphocytes immunology
Cytotoxicity, Immunologic genetics
Leukemia, Large Granular Lymphocytic immunology
Membrane Proteins physiology
Receptors, Immunologic physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 113
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 19075187
- Full Text :
- https://doi.org/10.1182/blood-2008-07-168245