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T Cell-Specific Deletion of the Inositol Phosphatase SHIP Reveals Its Role in Regulating Th1/Th2 and Cytotoxic Responses
Tatyana Tarasenko, Hemanta K. Kole, Anthony W. Chi, Margaret M. Mentink-Kane, Thomas A. Wynn and Silvia Bolland
Proceedings of the National Academy of Sciences of the United States of America
Vol. 104, No. 27 (Jul. 3, 2007), pp. 11382-11387
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25436123
Page Count: 6
You can always find the topics here!Topics: T lymphocytes, Cytokines, Eggs, Cell lines, Antibodies, Lymph nodes, T cell antigen receptors, Messenger RNA, Phosphorylation, Phosphatases
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The 5'-phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8⁺ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity.
Proceedings of the National Academy of Sciences of the United States of America © 2007 National Academy of Sciences