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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Adaptor Proteins, Signal Transducing / physiology*
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CD28 Antigens / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / pathology
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Cytotoxicity, Immunologic / genetics*
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Endothelial Cells / immunology
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Endothelial Cells / pathology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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K562 Cells
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Leukemia, Large Granular Lymphocytic / genetics
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Leukemia, Large Granular Lymphocytic / immunology*
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Leukemia, Large Granular Lymphocytic / metabolism
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Leukemia, Large Granular Lymphocytic / pathology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Membrane Proteins / physiology*
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Phosphatidylinositol 3-Kinases / metabolism
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Pulmonary Artery / immunology
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Pulmonary Artery / pathology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / metabolism
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Receptors, Immunologic / physiology*
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Receptors, Natural Killer Cell / metabolism
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Signal Transduction / genetics
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Tumor Cells, Cultured
Substances
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Adaptor Proteins, Signal Transducing
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CD28 Antigens
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HCST protein, human
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Membrane Proteins
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Receptors, Immunologic
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Receptors, Natural Killer Cell
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TYROBP protein, human
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Phosphatidylinositol 3-Kinases
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Extracellular Signal-Regulated MAP Kinases