Hu Caroline K, Venet Fabienne, Heffernan David S, Wang Yvonne L, Horner Brian, Huang Xin, Chung Chun-Shiang, Gregory Stephen H, Ayala Alfred
Shock-Trauma Research Laboratories, Division of Surgical Research, Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence, RI 02903, USA.
J Immunol. 2009 Feb 15;182(4):2467-75. doi: 10.4049/jimmunol.0801463.
NKT cells have been described as innate regulatory cells because of their rapid response to conserved glycolipids presented on CD1d via their invariant TCR. However, little is known about the contribution of the hepatic NKT cell to the development of a local and/or systemic immune response to acute septic challenge (cecal ligation and puncture (CLP)). We found not only that mice deficient in invariant NKT cells (Jalpha18(-/-)) had a marked attenuation in CLP-induced mortality, but also exhibited an oblation of the systemic inflammatory response (with little effect on splenic/peritoneal immune responsiveness). Flow cytometric data indicated that following CLP, there was a marked decline in the percentage of CD3(+)alpha-galactosylceramide CD1d tetramer(+) cells in the mouse C57BL/6J and BALB/c liver nonparenchymal cell population. This was associated with the marked activation of these cells (increased expression of CD69 and CD25) as well as a rise in the frequency of NKT cells positive for both Th1 and Th2 intracellular cytokines. In this respect, when mice were pretreated in vivo with anti-CD1d-blocking Ab, we observed not only that this inhibited the systemic rise of IL-6 and IL-10 levels in septic mice and improved overall septic survival, but that the CLP-induced changes in liver macrophage IL-6 and IL-10 expressions were inversely effected by this treatment. Together, these findings suggest that the activation of hepatic invariant NKT cells plays a critical role in regulating the innate immune/systemic inflammatory response and survival in a model of acute septic shock.
自然杀伤T细胞（NKT细胞）因其通过不变的T细胞受体（TCR）对CD1d上呈递的保守糖脂快速作出反应，而被描述为先天性调节细胞。然而，关于肝脏NKT细胞在急性脓毒症挑战（盲肠结扎和穿刺（CLP））的局部和/或全身免疫反应发展中的作用，人们了解甚少。我们发现，不仅缺乏不变NKT细胞的小鼠（Jalpha18基因敲除小鼠）在CLP诱导的死亡率方面有显著降低，而且还表现出全身炎症反应的减弱（对脾脏/腹膜免疫反应性影响很小）。流式细胞术数据表明，CLP后，小鼠C57BL/6J和BALB/c肝脏非实质细胞群体中CD3(+)α-半乳糖神经酰胺CD1d四聚体(+)细胞的百分比显著下降。这与这些细胞的显著激活（CD69和CD25表达增加）以及Th1和Th2细胞内细胞因子均呈阳性的NKT细胞频率升高有关。在这方面，当小鼠在体内用抗CD1d阻断抗体进行预处理时，我们不仅观察到这抑制了脓毒症小鼠体内IL-6和IL-10水平的全身升高并改善了整体脓毒症存活率，而且还观察到这种处理对CLP诱导的肝脏巨噬细胞IL-6和IL-10表达变化产生了相反的影响。总之，这些发现表明，肝脏不变NKT细胞的激活在调节急性脓毒症休克模型中的先天性免疫/全身炎症反应和存活率方面起着关键作用。
