Zheng Xincheng, Zhang Huiming, Yin Lijie, Wang Chyung-Ru, Liu Yang, Zheng Pan
Department of Surgery, Comprehensive Cancer Center, Program of Molecular Mechanism of Diseases, University of Michigan, Ann Arbor, Michigan, United States of America.
PLoS One. 2008 Jul 16;3(7):e2703. doi: 10.1371/journal.pone.0002703.
It has been demonstrated that the development of NKT cells requires CD1d. The contribution of costimulatory molecules in this process has not been studied. Here we show that in mice with targeted mutations of B7-1/2 and CD28, the TCRbeta(+)alpha-Galcer/CD1d(+) (iValpha14 NKT) subset is significantly reduced in the thymus, spleen and liver. This is mainly due to decreased cell proliferation; although increased cell death in the thymi of CD28-deficient mice was also observed. Moreover, in the B7-1/2- and CD28-deficient mice, we found a decreased percentage of the CD4(-)NK1.1(+) subset and a correspondingly increased portion of the CD4(+)NK1.1(-) subset. In addition, the mice with a targeted mutation of either B7 or CD28 had a reduced susceptibility to Con A induced hepatitis, which is known to be mediated by NKT cells. Our results demonstrate that the development, maturation and function of NKT cell are modulated by the costimulatory pathway and thus expand the horizon of costimulation into NKT, which is widely viewed as a bridge between innate and adaptive immunity. As such, costimulation may modulate all major branches of cell-mediated immunity, including T cells, NK cells and NKT cells.
已证实NKT细胞的发育需要CD1d。共刺激分子在此过程中的作用尚未得到研究。在此我们表明，在B7-1/2和CD28发生靶向突变的小鼠中，TCRβ(+)α-Galcer/CD1d(+)（iValpha14 NKT）亚群在胸腺、脾脏和肝脏中显著减少。这主要是由于细胞增殖减少；尽管在CD28缺陷小鼠的胸腺中也观察到细胞死亡增加。此外，在B7-1/2和CD28缺陷的小鼠中，我们发现CD4(-)NK1.1(+)亚群的百分比降低，而CD4(+)NK1.1(-)亚群的比例相应增加。另外，B7或CD28发生靶向突变的小鼠对已知由NKT细胞介导的刀豆蛋白A诱导的肝炎的易感性降低。我们的结果表明，NKT细胞的发育、成熟和功能受共刺激途径调节，从而将共刺激的范围扩展到NKT细胞，NKT细胞被广泛视为固有免疫和适应性免疫之间的桥梁。因此，共刺激可能调节细胞介导免疫的所有主要分支，包括T细胞、NK细胞和NKT细胞。
