Ma Juan, He Peng, Zhao Chuanfang, Ren Quanzhong, Dong Zheng, Qiu Jiahuang, Jing Yang, Liu Sijin, Du Yuguo
State Key Laboratory of Environmental Chemistry and Ecotoxicology Research Center for Eco-Environmental Sciences Chinese Academy of Sciences Beijing 100085 P. R. China.
School of Environmental Sciences University of Chinese Academy of Sciences Beijing 100049 P. R. China.
Adv Sci (Weinh). 2020 Jun 8;7(14):2000609. doi: 10.1002/advs.202000609. eCollection 2020 Jul.
Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. -galactosylceramide (-GalCer, KRN7000), a well-studied Th1-polarizer, simultaneously induces helper T cell 2 (Th2)-type responses, which is a major drawback for its clinical applications. Based on surflex-docking computation, -GalCer-diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between -GalCer-diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self-activation, as reflected by tight binding of the T-cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL-12) and interferon- (IFN-). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1-type cytokine profile ex vivo and in vivo. Different from KRN7000, -GalCer-diol markedly boosts the expansion of the CD11b subpopulation and enhances IFN- content in CD11b cells. These reinforced Th1-type responses collectively endow -GalCer-diol more robust antitumor activity in a xenograft animal model using B16-F10 melanoma cells. Together, the data demonstrate a new mechanism through which -GalCer-diol induces stronger Th1-type responses by stimulating CD11b leukocyte expansion and DC-conducted CD1d-restricted and TCR-mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.
选择性辅助性T细胞1（Th1）启动激动剂是免疫治疗各种疾病的一个有前景的研究领域。α-半乳糖神经酰胺（α-GalCer，KRN7000）是一种经过充分研究的Th1极化剂，同时会诱导辅助性T细胞2（Th2）型反应，这是其临床应用的一个主要缺点。基于表面柔性对接计算，设计并合成了在酰基链中添加了羟基的α-GalCer-二醇。结构分析表明，α-GalCer-二醇与分化簇1d（CD1d）之间具有更强的亲和力，导致树突状细胞（DC）的抗原呈递增强以及自身激活，这通过T细胞受体（TCR）/KRN7000/CD1d三元复合物的紧密结合以及白细胞介素12（IL-12）和干扰素-γ（IFN-γ）的产量升高得以体现。因此，不变自然杀伤T细胞（iNKT）被激活，并在体外和体内表现出改善的Th1型细胞因子谱。与KRN7000不同，α-GalCer-二醇显著促进CD11b亚群的扩增，并提高CD11b细胞中的IFN-γ含量。这些增强的Th1型反应共同赋予α-GalCer-二醇在使用B16-F10黑色素瘤细胞的异种移植动物模型中更强的抗肿瘤活性。总之，数据证明了一种新机制，即α-GalCer-二醇通过刺激CD11b白细胞扩增以及DC介导的CD1d限制性和TCR介导的iNKT激活来诱导更强的Th1型反应。因此，本研究可能有助于新型Th1启动激动剂的开发。
