Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of alpha-galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells.

Abstract

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.

• Authors: Jun Okajo, Yoriaki Kaneko, Yoji Murata, Takeshi Tomizawa, Chie Okuzawa, Yasuyuki Saito, Yuka Kaneko, Tomomi Ishikawa-Sekigami, Hideki Okazawa, Hiroshi Ohnishi, Takashi Matozaki, Yoshihisa Nojima
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 10 Pg. 6164-72 (May 15 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17475843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD1
• Antigens, CD1d
• CD11c Antigen
• Galactosylceramides
• Ptpns1 protein, mouse
• Receptors, Immunologic
• alpha-galactosylceramide

Topics

• Animals
• Antigens, CD1 (biosynthesis, genetics)
• Antigens, CD1d
• CD11c Antigen (biosynthesis, genetics)
• Cytotoxicity, Immunologic (genetics)
• Dendritic Cells (immunology, metabolism)
• Galactosylceramides (administration & dosage)
• Killer Cells, Natural (enzymology, immunology)
• Lung Neoplasms (genetics, immunology, prevention & control, secondary)
• Lymphocyte Activation (genetics)
• Melanoma, Experimental (genetics, immunology, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Receptors, Immunologic (biosynthesis, deficiency, genetics, physiology)
• T-Lymphocyte Subsets (enzymology, immunology)
• Th1 Cells (enzymology, immunology, metabolism)
• Th2 Cells (enzymology, immunology, metabolism)
• src Homology Domains (genetics, immunology)