Gestation staae-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss
Gestation staae-dependent mechanisms of invariant natural killer T cell-mediated pregnancy loss
复制标题
DOI：
10.1073/pnas.0511025103
复制
发表时间：
2006-03-21
影响因子：
11.1
通讯作者：
Strominger, JL
中科院分区：
文献类型：
--
作者：
Boyson, JE;Nagarkatti, N;Strominger, JL
使用 Cd1d 配体 α-半乳糖苷神经酰胺 (α GalCer) 刺激 CD1d 限制性半不变自然杀伤 T 细胞，通过涉及 TNF、IFN-γ 和穿孔素的不明确机制诱导小鼠妊娠流产。在本文中，我们证明在妊娠早期，α GalCer 以穿孔素依赖性方式有效诱导 C57BL/6J 和 BALB/cJ 小鼠妊娠流产。相比之下，在妊娠中期，不再需要穿孔素来治疗流产。伴随着妊娠中期穿孔素需求的丧失，出现了对 α GalCer 诱导的妊娠丢失的易感性的菌株依赖性变化。怀孕的 C57BL/6J 小鼠在妊娠中期仍然对 α GalCer 敏感，而怀孕的 BALB/cJ 小鼠对其作用具有抵抗力。与耐药 BALB/cJ 菌株相比，易感 C57BL/6J 菌株中妊娠中期流产与显着升高的血清细胞因子水平相关，包括 TNF 和 IL-2。因此，妊娠阶段定义了两种不同的妊娠丢失机制：在妊娠早期起作用的穿孔素依赖性机制和在妊娠中期后起作用的不依赖于穿孔素、细胞因子主导的机制。
Stimulation of CD1d-restricted semiinvariant natural killer T cells by using the Cd1d ligand alpha-galactosylceramide (alpha GalCer) induces pregnancy loss in mice through an ill-defined mechanism involving TNF, IFN-gamma, and perforin. In this article, we demonstrate that during early gestation, alpha GalCer efficiently induced pregnancy loss in C57BL/6J and BALB/cJ mice in a perforin-dependent manner. In contrast, during midgestation perforin was no longer required for pregnancy loss. Concomitant with the loss of a perforin requirement at midgestation was the emergence of strain-dependent variations in susceptibility to alpha GalCer-induced pregnancy loss. Whereas pregnant C57BL/6J mice remained susceptible to alpha GalCer at midgestation, pregnant BALB/cJ mice were resistant to its effects. Pregnancy loss during midgestation was correlated with dramatically higher serum cytokine levels, including TNF and IL-2, in the susceptible C57BL/6J strain compared with the resistant BALB/cJ strain. Thus, the stage of gestation defined two distinct mechanisms of pregnancy loss: a perforin-dependent mechanism operating at early gestation and a perforin-independent, cytokine-dominated mechanism operating after midgestation.