Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells
Regulation by Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 of α-galactosylceramide-induced antimetastatic activity and Th1 and Th2 responses of NKT cells
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DOI：
10.4049/jimmunol.178.10.6164
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发表时间：
2007-05-15
影响因子：
4.4
通讯作者：
Nojima, Yoshihisa
中科院分区：
文献类型：
--
作者：
Okajo, Jun;Kaneko, Yoriaki;Nojima, Yoshihisa
CD1d介导的树突状细胞(DC)上的α-半乳糖神经酰胺(α-GalCer)与NKT细胞不变的TCR相互作用可激活NKT细胞。现在，我们利用表达突变形式的SHPS-1的小鼠，研究了含有Src同源2结构域的蛋白酪氨酸磷酸酶底物1(SHPS-1)在调节NKT细胞中的作用。SHPS-1是一种在DC上大量表达的跨膜蛋白。与野生型(WT)小鼠相比，SHPS-1突变小鼠对实验性肺转移的抑制作用明显减弱。过继转移SHPS-1突变小鼠的α-GalCer冲击的DC所产生的抗肿瘤转移作用也比WT DC明显减弱。与WT细胞相比，SHPS-1突变小鼠脾细胞和肝单个核细胞对α-GalCer刺激产生的干扰素-γ和IL-4的产生以及体外细胞增殖均明显减弱。此外，SHPS-1突变小鼠的CD11c(+)DO和α-GalCer孵育的单个核细胞产生的干扰素-γ和IL-4的量明显低于与WT小鼠的α-GalCer和CD11c(+)DC孵育的结果。因此，DO上的SHPS-1似乎对α-GalCer诱导的NKT细胞的抗肿瘤活性和Th1和Th2反应是必不可少的。此外，我们最近的发现表明，DO上的SHPS-1对于免疫杂志，2007年，178：6164-617.2的CD_4(+)T细胞的启动也是必不可少的。
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 a-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 a-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 a-GalCer and CD11c(+) DO from SHPS-1 mutant mice produced markedly smaller amounts of IFN-gamma and IL-4 than did those incubated with a-GalCer and CD11c(+) DCs from WT mice. SHPS-1 on DO 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 DO is also essential for the priming of CD4(+) T cells by Ms. The Journal of Immunology, 2007, 178: 6164-617.2.