title: A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia.
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.
authors.affiliation: Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Chen
authors.forename: Fanqi
authors.initials: F
authors.lastname: Bai
authors.forename: Lubomir
authors.initials: L
authors.lastname: Sokol
authors.forename: Junmin
authors.initials: J
authors.lastname: Zhou
authors.forename: Amy
authors.initials: A
authors.lastname: Ren
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Painter
authors.forename: Jinhong
authors.initials: J
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Sallman
authors.forename: Y Ann
authors.initials: YA
authors.lastname: Chen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Yoder
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
authors.forename: Pearlie K
authors.initials: PK
authors.lastname: Epling-Burnette
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011651:Pulmonary Artery / Q000276:immunology / Q000473:pathology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018106:CD28 Antigens; C120528:HCST protein, human; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; C110546:TYROBP protein, human; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases