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-Galactosylceramide-Induced Antimetastatic Activity and Th1 and Th2 Responses of NKT Cells1
* Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan; and
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, Japan
Interaction of 
-galactosylceramide (-GalCer) presented by CD1d on dendritic cells (DCs) with the invariant TCR of NKT cells activates NKT cells. We have now investigated the role of Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 (SHPS-1), a transmembrane protein abundantly expressed on DCs, in regulation of NKT cells with the use of mice that express a mutant form of SHPS-1. The suppression by -GalCer of experimental lung metastasis was markedly attenuated in SHPS-1 mutant mice compared with that apparent in wild-type (WT) mice. The antimetastatic effect induced by adoptive transfer of -GalCer-pulsed DCs from SHPS-1 mutant mice was also reduced compared with that apparent with WT DCs. Both the production of IFN-
and IL-4 as well as cell proliferation in response to -GalCer in vitro were greatly attenuated in splenocytes or hepatic mononuclear cells from SHPS-1 mutant mice compared with the responses of WT cells. Moreover, CD4+ mononuclear cells incubated with -GalCer and CD11c+ DCs from SHPS-1 mutant mice produced markedly smaller amounts of IFN- and IL-4 than did those incubated with -GalCer and CD11c+ DCs from WT mice. SHPS-1 on DCs thus appears to be essential for -GalCer-induced antimetastatic activity and Th1 and Th2 responses of NKT cells. Moreover, our recent findings suggest that SHPS-1 on DCs is also essential for the priming of CD4+ T cells by DCs.
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1 This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas Cancer, a Grant-in-Aid for Scientific Research (B) and (C), and a grant from the 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
2 Address correspondence and reprint requests to Dr. Takashi Matozaki, Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-Machi, Maebashi, Gunma 371-8512, Japan. E-mail address: matozaki{at}showa.gunma-u.ac.jp
3 Abbreviations used in this paper: -GalCer, -galactosylceramide; DC, dendritic cell; Eu, europium; LDF, low-density fraction; MNC, mononuclear cell; SHP, Src homology 2 domain-containing protein tyrosine phosphatase; SHPS-1, SHP substrate-1; TDA, 2,2'':6',2''-terpyridine-6,6''-dicarboxylic acid; WT, wild type.
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