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.
A critical role for DAP10 and DAP12 in CD8+ T cell-mediated tissue damage in
large granular lymphocyte leukemia
Xianghong Chen1,*, Fanqi Bai1,*, Lubomir Sokol2, Junmin Zhou1, Amy Ren1, Jeffrey
S. Painter1, Jinhong Liu1, David A. Sallman1, Y. Ann Chen1, Jeffrey A. Yoder3,
Julie Y. Djeu1,, Thomas P. Loughran4,, Pearlie K. Epling-Burnette1,2,5,, and
Sheng Wei1,
1 Immunology Program and 2 Malignant Hematology Program, H. Lee Moffitt Cancer
Center and Research Institute, Tampa, FL; 3 Department of Molecular Biomedical
Sciences and Center for Comparative Medicine and Translational Research, College
of Veterinary Medicine, North Carolina State University, Raleigh; 4 Penn State
Cancer Institute, Penn State College of Medicine, Hershey; and 5 James A. Haley
VA Hospital, Tampa, FL


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 with
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.



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