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A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia.

Authors: Chen, X  Bai, F  Sokol, L  Zhou, J  Ren, A  Painter, JS  Liu, J  Sallman, DA  Chen, YA  Yoder, JA  Djeu, JY  Loughran, TP  Epling-Burnette, PK  Wei, S 
Citation: Chen X, etal., Blood. 2009 Apr 2;113(14):3226-34. Epub 2008 Dec 15.
Pubmed: (View Article at PubMed) PMID:19075187
DOI: Full-text: DOI:10.1182/blood-2008-07-168245

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.

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CRRD Object Information
CRRD ID: 5131619
Created: 2011-05-05
Species: All species
Last Modified: 2011-05-05
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.