PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells.
PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells.
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DOI：
10.4049/jimmunol.0803648
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发表时间：
2009-03-01
期刊：
影响因子：
--
通讯作者：
Kaer LV
中科院分区：
文献类型：
--
作者：
Parekh VV;Lalani S;Kim S;Halder R;Azuma M;Yagita H;Kumar V;Wu L;Kaer LV
不变自然杀伤T（iNKT）细胞识别糖脂抗原，例如由CD1d蛋白呈递的源自海洋海绵的鞘糖脂α-半乳糖神经酰胺（αGalCer）。在体内用αGalCer激活iNKT细胞会导致大量细胞因子产生，随后获得无反应性表型。在此，我们研究了导致αGalCer诱导的iNKT细胞无反应性建立的机制。我们发现αGalCer激活的iNKT细胞在其细胞表面迅速上调抑制性共刺激受体程序性死亡受体1（PD - 1）的表达，并且这种增加的表达至少持续一个月。在αGalCer治疗时阻断PD - 1与其配体PD - L1和PD - L2之间的相互作用可阻止iNKT细胞无反应性的诱导，但无法逆转已建立的iNKT细胞无反应性。一致地，向PD - 1缺陷型小鼠注射αGalCer未能诱导iNKT细胞无反应性。然而，阻断PD - 1:PD - L通路未能阻止细菌或硫苷脂诱导的iNKT细胞无反应性，这表明存在iNKT细胞耐受的其他机制。最后，我们表明阻断PD - 1:PD - L相互作用增强了αGalCer的抗转移活性。总之，我们的研究结果揭示了PD - 1:PD - L共刺激通路在αGalCer介导的iNKT细胞无反应性诱导中具有关键作用，该通路可作为免疫疗法开发的靶点。
Invariant natural killer T (iNKT) cells recognize glycolipid antigens such as the marine sponge-derived glycosphingolipid α-galactosylceramide (αGalCer) presented by the CD1d protein. In vivo activation of iNKT cells with αGalCer results in robust cytokine production followed by the acquisition of an anergic phenotype. Here, we have investigated mechanisms responsible for the establishment of αGalCer-induced iNKT cell anergy. We found that αGalCer-activated iNKT cells rapidly upregulated expression of the inhibitory co-stimulatory receptor programmed death (PD)-1 at their cell surface, and this increased expression was retained for at least one month. Blockade of the interaction between PD-1 and its ligands, PD-L1 and PD-L2, at the time of αGalCer treatment prevented the induction iNKT cell anergy, but was unable to reverse established iNKT cell anergy. Consistently, injection of αGalCer into PD-1-deficient mice failed to induce iNKT cell anergy. However, blockade of the PD-1:PD-L pathway failed to prevent bacterial- or sulfatide-induced iNKT cell anergy, suggesting additional mechanisms of iNKT cell tolerance. Finally, we showed that blockade of PD-1:PD-L interactions enhanced the antimetastatic activities of αGalCer. Collectively, our findings reveal a critical role for the PD-1:PD-L costimulatory pathway in the αGalCer-mediated induction of iNKT cell anergy that can be targeted for the development of immunotherapies.
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DOI：
10.1084/jem.20061577
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fife BT;Guleria I;Gubbels Bupp M;Eagar TN;Tang Q;Bour-Jordan H;Yagita H;Azuma M;Sayegh MH;Bluestone JA
通讯作者：
Bluestone JA
影响因子：
15.9
作者：
Halder, Ramesh C.;Aguilera, Carlos;Kumar, Vipin
通讯作者：
Kumar, Vipin
影响因子：
30.5
作者：
Kinjo, Yuki;Tupin, Emmanuel;Kronenberg, Mitchell
通讯作者：
Kronenberg, Mitchell
影响因子：
4.4
作者：
Ito, T;Ueno, T;Najafian, N
通讯作者：
Najafian, N
影响因子：
32.4
作者：
Butte, Manish J.;Keir, Mary E.;Freeman, Gordon J.
通讯作者：
Freeman, Gordon J.