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Science 295 (5562): 2094-2097

Copyright © 2002 by the American Association for the Advancement of Science

Influence of SHIP on the NK Repertoire and Allogeneic Bone Marrow Transplantation

Jia-Wang Wang,1* Julie M. Howson,1* Tomar Ghansah,1* Caroline Desponts,1 John M. Ninos,1 Sarah L. May,1 Kim H. T. Nguyen,1 Noriko Toyama-Sorimachi,2 William G. Kerr1dagger

Natural killer cell (NK) receptors for major histocompatibility complex (MHC) class I influence engraftment and graft-versus-tumor effects after allogeneic bone marrow transplantation. We find that SH2-containing inositol phosphatase (SHIP) influences the repertoire of NK receptors. In adult SHIP-/- mice, the NK compartment is dominated by cells that express two inhibitory receptors capable of binding either self or allogeneic MHC ligands. This promiscuous repertoire has significant functional consequences, because SHIP-/- mice fail to reject fully mismatched allogeneic marrow grafts and show enhanced survival after such transplants. Thus, SHIP plays an important role in two processes that limit the success of allogeneic marrow transplantation: graft rejection and graft-versus-host disease.

1 Immunology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, and Departments of Interdisciplinary Oncology and Biochemistry, University of South Florida, Tampa, FL 33612, USA.
2 Department of Immune Regulation, Tokyo Medical and Dental University, Tokyo 113-8150, Japan.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: kerrw{at}

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R. Trotta, L. Chen, S. Costinean, S. Josyula, B. L. Mundy-Bosse, D. Ciarlariello, C. Mao, E. L. Briercheck, K. K. McConnell, A. Mishra, et al. (2013)
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J. A. Wahle, K. H. T. Paraiso, R. D. Kendig, H. R. Lawrence, L. Chen, J. Wu, and W. G. Kerr (2007)
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H. Kishimoto, T. Ohteki, N. Yajima, K. Kawahara, M. Natsui, S. Kawarasaki, K. Hamada, Y. Horie, Y. Kubo, S. Arase, et al. (2007)
Blood 109, 3316-3324
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M. S. Tessmer, C. Fugere, F. Stevenaert, O. V. Naidenko, H. J. Chong, G. Leclercq, and L. Brossay (2007)
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J. Immunol. 178, 2893-2900
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F. Gays, J. G. Aust, D. M. Reid, J. Falconer, N. Toyama-Sorimachi, P. R. Taylor, and C. G. Brooks (2006)
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   Abstract »    Full Text »    PDF »
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J. Regunathan, Y. Chen, S. Kutlesa, X. Dai, L. Bai, R. Wen, D. Wang, and S. Malarkannan (2006)
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J. A. Wahle, K. H. T. Paraiso, A. L. Costello, E. L. Goll, C. L. Sentman, and W. G. Kerr (2006)
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J. Immunol. 176, 4716-4729
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Phil Trans R Soc B 360, 1747-1767
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IFN Regulatory Factor-2 Deficiency Revealed a Novel Checkpoint Critical for the Generation of Peripheral NK Cells.
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   Abstract »    Full Text »    PDF »
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R. Trotta, R. Parihar, J. Yu, B. Becknell, J. Allard II, J. Wen, W. Ding, H. Mao, S. Tridandapani, W. E. Carson, et al. (2005)
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J. Immunol. 173, 7324-7330
   Abstract »    Full Text »    PDF »
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K. Beider, A. Nagler, O. Wald, S. Franitza, M. Dagan-Berger, H. Wald, H. Giladi, S. Brocke, J. Hanna, O. Mandelboim, et al. (2003)
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