Silk Jonathan D, Salio Mariolina, Reddy B Gopal, Shepherd Dawn, Gileadi Uzi, Brown James, Masri S Hajar, Polzella Paolo, Ritter Gerd, Besra Gurdyal S, Jones E Yvonne, Schmidt Richard R, Cerundolo Vincenzo
Tumour Immunology Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK.
J Immunol. 2008 May 15;180(10):6452-6. doi: 10.4049/jimmunol.180.10.6452.
Invariant NKT cells (iNKT cells) recognize CD1d/glycolipid complexes. We demonstrate that the nonglycosidic compound threitolceramide efficiently activates iNKT cells, resulting in dendritic cell (DC) maturation and the priming of Ag-specific T and B cells. Threitolceramide-pulsed DCs are more resistant to iNKT cell-dependent lysis than alpha-galactosylceramide-pulsed DCs due to the weaker affinity of the human iNKT TCR for CD1d/ threitolceramide than CD1d/alpha-galactosylceramide complexes. iNKT cells stimulated with threitolceramide also recover more quickly from activation-induced anergy. Kinetic and functional experiments showed that shortening or lengthening the threitol moiety by one hydroxymethylene group modulates ligand recognition, as human and murine iNKT cells recognize glycerolceramide and arabinitolceramide differentially. Our data broaden the range of potential iNKT cell agonists. The ability of these compounds to assist the priming of Ag-specific immune responses while minimizing iNKT cell-dependent DC lysis makes them attractive adjuvants for vaccination strategies.
不变自然杀伤T细胞（iNKT细胞）识别CD1d/糖脂复合物。我们证明，非糖苷化合物苏糖醇神经酰胺可有效激活iNKT细胞，导致树突状细胞（DC）成熟以及抗原特异性T细胞和B细胞的致敏。由于人iNKT TCR对CD1d/苏糖醇神经酰胺的亲和力低于CD1d/α-半乳糖神经酰胺复合物，因此苏糖醇神经酰胺脉冲处理的DC比α-半乳糖神经酰胺脉冲处理的DC对iNKT细胞依赖性裂解更具抗性。用苏糖醇神经酰胺刺激的iNKT细胞也能更快地从激活诱导的无反应状态中恢复。动力学和功能实验表明，通过一个羟亚甲基缩短或延长苏糖醇部分可调节配体识别，因为人和小鼠iNKT细胞对甘油神经酰胺和阿拉伯糖醇神经酰胺的识别存在差异。我们的数据拓宽了潜在的iNKT细胞激动剂的范围。这些化合物在辅助抗原特异性免疫反应致敏的同时将iNKT细胞依赖性DC裂解降至最低的能力，使其成为疫苗接种策略中有吸引力的佐剂。
