Tran Kenny K, Shen Hong
Department of Chemical Engineering, University of Washington, 353 Benson Hall, Box 351750, Seattle, WA 98195, USA.
Biomaterials. 2009 Mar;30(7):1356-62. doi: 10.1016/j.biomaterials.2008.11.034. Epub 2008 Dec 16.
Vaccines able to stimulate CD8(+) T cells are crucial in controlling a broad range of infectious diseases and tumors. To induce effective CD8(+) T cell responses, exogenous antigen has to be cross-presented onto major histocompatibility complex (MHC) class I molecules by dendritic cells. Although particle size has been recognized as a critical factor of vaccine design, it is unclear how the size of vaccine carriers impacts the intracellular processing of exogenous antigen and cross-presentation onto MHC class I molecules. In this study, by using polystyrene beads with narrowly defined sizes as model antigen carriers, we demonstrate that particle size mediates the efficiency of cross-presentation of exogenous antigens. By examining the intracellular trafficking, kinetics of phagosomal pH and degradation of antigens bounded to beads, we illustrate the possible mechanisms attributed to the profound effect of particle size on the efficiency of cross-presentation. Antigen bounded to 50 nm beads was shuttled rapidly to an acidic environment within half an hour post-exposure to cells, leading to its rapid and unregulated degradation and inefficient cross-presentation. In contrast, antigen bounded to 500 nm and 3 microm beads remained in a more neutral environment, which preserved the majority of antigens, leaving it available for the generation of peptides to be loaded onto MHC class I molecules. We conclude that the size of antigen carriers plays a critical role in directing antigen to the class I antigen presentation pathway. Our results, together with previous in vivo studies on the effect of particle size on CD8(+) T cell responses, provide insight into the rational design of vaccines for the stimulation of cell-mediated immunity.
能够刺激CD8(+) T细胞的疫苗对于控制多种传染病和肿瘤至关重要。为了诱导有效的CD8(+) T细胞反应，外源抗原必须由树突状细胞交叉呈递到主要组织相容性复合体（MHC）I类分子上。尽管颗粒大小已被认为是疫苗设计的关键因素，但尚不清楚疫苗载体的大小如何影响外源抗原的细胞内加工以及向MHC I类分子的交叉呈递。在本研究中，我们使用尺寸定义明确的聚苯乙烯珠作为模型抗原载体，证明颗粒大小介导了外源抗原交叉呈递的效率。通过检查细胞内运输、吞噬体pH值的动力学以及与珠子结合的抗原的降解情况，我们阐述了颗粒大小对交叉呈递效率产生深远影响的可能机制。与细胞接触半小时后，与50纳米珠子结合的抗原迅速被转运到酸性环境中，导致其快速且无规律地降解以及交叉呈递效率低下。相比之下，与500纳米和3微米珠子结合的抗原则保留在更中性的环境中，这使得大多数抗原得以保存，从而可用于生成加载到MHC I类分子上的肽段。我们得出结论，抗原载体的大小在引导抗原进入I类抗原呈递途径中起着关键作用。我们的数据，连同先前关于颗粒大小对CD8(+) T细胞反应影响的体内研究，为合理设计用于刺激细胞介导免疫的疫苗提供了见解。
