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Blood, 2 April 2009, Vol. 113, No. 14, pp. 3226-3234. Prepublished online as a Blood First Edition Paper on December 15, 2008; DOI 10.1182/blood-2008-07-168245. This Article Full Text (PDF) All Versions of this Article: blood-2008-07-168245v1 113/14/3226    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, X. Articles by Wei, S. Search for Related Content PubMed PubMed Citation Articles by Chen, X. Articles by Wei, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 14, 2008 Accepted November 23, 2008 A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in large granular lymphocyte leukemia Xianghong Chen, Fanqi Bai, Lubomir Sokol, Junmin Zhou, Amy Ren, Jeffrey S Painter, Jinhong Liu, David A Sallman, Y. Ann Chen, Jeffrey A Yoder, Julie Y Djeu, Thomas P Loughran Jr., P.K Epling-Burnette, and Sheng Wei* Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States Malignant Hematology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, United States James A. Haley VA Hospital, Tampa, FL, United States * Corresponding author; email: sheng.wei{at}moffitt.org. 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+CD28null phenotype induce these clinical manifestations through direct destruction of normal tissue. Compared to CD8+CD28null T cells from healthy controls, CD8+CD28null 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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