Silk Jonathan D, Hermans Ian F, Gileadi Uzi, Chong Tsung Wen, Shepherd Dawn, Salio Mariolina, Mathew Bini, Schmidt Richard R, Lunt Sarah Jane, Williams Kaye J, Stratford Ian J, Harris Adrian L, Cerundolo Vincenzo
Tumour Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
J Clin Invest. 2004 Dec;114(12):1800-11. doi: 10.1172/JCI22046.
Activation of invariant CD1d-dependent NK T cells (iNKT cells) in vivo through administration of the glycolipid ligand alpha-galactosylceramide (alpha-GalCer) or the sphingosine-truncated alpha-GalCer analog OCH leads to CD40 signaling as well as the release of soluble molecules including type 1 and gamma interferons that contribute to DC maturation. This process enhances T cell immunity to antigens presented by the DC. The adjuvant activity is further amplified if APCs are stimulated through Toll-like receptor 4, suggesting that iNKT cell signals can amplify maturation induced by microbial stimuli. The adjuvant activity of alpha-GalCer enhances both priming and boosting of CD8(+) T cells to coadministered peptide or protein antigens, including a peptide encoding the clinically relevant, HLA-A2-restricted epitope of the human tumor antigen NY-ESO-1. Importantly, alpha-GalCer was used to induce CD8(+) T cells to antigens delivered orally, despite the fact that this route of administration is normally associated with blunted responses. Only T cell responses induced in the presence of iNKT cell stimulation, whether by the i.v. or oral route, were capable of eradicating established tumors. Together these data highlight the therapeutic potential of iNKT cell ligands in vaccination strategies, particularly "heterologous prime-boost" strategies against tumors, and provide evidence that iNKT cell stimulation may be exploited in the development of oral vaccines.
通过给予糖脂配体α-半乳糖神经酰胺（α-GalCer）或鞘氨醇截短的α-GalCer类似物OCH在体内激活不变的CD1d依赖性自然杀伤T细胞（iNKT细胞），会导致CD40信号传导以及包括1型干扰素和γ干扰素在内的可溶性分子的释放，这些分子有助于树突状细胞（DC）成熟。这一过程增强了T细胞对DC呈递抗原的免疫反应。如果通过Toll样受体4刺激抗原呈递细胞（APC），佐剂活性会进一步增强，这表明iNKT细胞信号可以放大由微生物刺激诱导的成熟。α-GalCer的佐剂活性增强了CD8(+) T细胞对共同给予的肽或蛋白质抗原（包括编码人类肿瘤抗原NY-ESO-1的临床相关、HLA-A2限制性表位的肽）的初次免疫和加强免疫。重要的是，尽管口服这种给药途径通常会导致反应减弱，但α-GalCer仍被用于诱导CD8(+) T细胞对口服递送的抗原产生反应。只有在iNKT细胞刺激存在下诱导的T细胞反应，无论是通过静脉注射还是口服途径，才有能力根除已形成的肿瘤。这些数据共同突出了iNKT细胞配体在疫苗接种策略中的治疗潜力，特别是针对肿瘤的“异源初免-加强”策略，并提供了证据表明iNKT细胞刺激可用于口服疫苗的开发。
