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International Immunology Advance Access originally published online on January 17, 2008
International Immunology 2008 20(3):345-352; doi:10.1093/intimm/dxm150
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Distinct regulatory functions of SLP-76 and MIST in NK cell cytotoxicity and IFN-{gamma} production

Shinya Hidano1, Hiroki Sasanuma1, Keiko Ohshima1, Ken-ichiro Seino2, Lalit Kumar3,4, Katsuhiko Hayashi5, Masaki Hikida6, Tomohiro Kurosaki6, Masaru Taniguchi2, Raif S. Geha3,4, Daisuke Kitamura5 and Ryo Goitsuka1

1 Division of Development and Aging, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
2 Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Tsurumi, Kanagawa 230-0045, Japan
3 Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
4 Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA
5 Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan
6 Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, Tsurumi, Kanagawa 230-0045, Japan

Correspondence to: R. Goitsuka; E-mail: ryogoi{at}rs.noda.tus.ac.jp

Activation of NK cells is triggered by multiple receptors. We demonstrate here that SLP-76 is required for CD16- and NKG2D-mediated NK cell cytotoxicity, while MIST negatively regulates these responses in an SLP-76-dependent manner. Exceptionally, MIST acts as a positive regulator of cytotoxicity against YAC-1 cells, although SLP-76 plays a more key role. SLP-76 acts as a dominant positive regulator for both NKG2D-mediated and YAC-1 cell-triggered IFN-{gamma} production. Although NKG2D-mediated IFN-{gamma} production depends on phospholipase C (PLC) {gamma}2, YAC-1 cell-triggered IFN-{gamma} production is PLC{gamma}2- and Syk/ZAP-70 independent and nuclear factor-kappa B mediated. SLP-76 is required for this process in the presence of MIST but is dispensable in the absence of MIST. Thus, YAC-1 cell-triggered NKG2D-independent IFN-{gamma} production appears to be regulated by SLP-76-dependent and -independent pathways, in which the latter is negatively regulated by MIST. Taken together, these results suggest that SLP-76 and MIST distinctly but interactively regulate NK cell cytotoxicity and IFN-{gamma} production.

Keywords: adaptor, NK cell, signal transduction

Transmitting editor: K. Okumura

Received 6 August 2007, accepted 12 December 2007.


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