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.
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.
Okajo
Jun
J
Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
Kaneko
Yoriaki
Y
Murata
Yoji
Y
Tomizawa
Takeshi
T
Okuzawa
Chie
C
Saito
Yasuyuki
Y
Kaneko
Yuka
Y
Ishikawa-Sekigami
Tomomi
T
Okazawa
Hideki
H
Ohnishi
Hiroshi
H
Matozaki
Takashi
T
Nojima
Yoshihisa
Y
D000818:Animals; D018949:Antigens, CD1 / Q000096:biosynthesis / Q000235:genetics; D055610:Antigens, CD1d; D039521:CD11c Antigen / Q000096:biosynthesis / Q000235:genetics; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005699:Galactosylceramides / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000201:enzymology / Q000276:immunology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology; D018417:Th1 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology
D018949:Antigens, CD1; D055610:Antigens, CD1d; D039521:CD11c Antigen; D005699:Galactosylceramides; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; C493154:alpha-galactosylceramide