Regulation by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 of -Galactosylceramide-Induced Antimetastatic Activity and Th1 and Th2 Responses of Nkt Cells

Okajo, J.; Kaneko, Y.; Murata, Y.; Tomizawa, T.; Okuzawa, C.; Saito, Y.; Kaneko, Y.; Ishikawa-Sekigami, T.; Okazawa, H.; Ohnishi, H.; Matozaki, T.; Nojima, Y.

The Journal of Immunology 178(10): 6164-6172


DOI: 10.4049/jimmunol.178.10.6164
Accession: 068490448

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Interaction of alpha-galactosylceramide (alpha-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 alpha-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 alpha-GalCer-pulsed DCs from SHPS-1 mutant mice was also reduced compared with that apparent with WT DCs. Both the production of IFN-gamma and IL-4 as well as cell proliferation in response to alpha-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 alpha-GalCer and CD11c+ DCs from SHPS-1 mutant mice produced markedly smaller amounts of IFN-gamma and IL-4 than did those incubated with alpha-GalCer and CD11c+ DCs from WT mice. SHPS-1 on DCs thus appears to be essential for alpha-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.