Hotblack Alastair, Seshadri Sara, Zhang Lei, Hamrang-Yousefi Sahar, Chakraverty Ronjon, Escors David, Bennett Clare L
Institute for Immunity and Transplantation, University College London, London NW3 2PF, UK.
Institute for Immunity and Transplantation, University College London, London NW3 2PF, UK; Cancer Institute, University College London, London WC1E 6DD, UK.
Mol Ther. 2017 Feb 1;25(2):504-511. doi: 10.1016/j.ymthe.2016.11.001.
Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protective T cell immunity in disease models. Dendritic cells (DCs) acquire antigen at sites of vaccination and migrate to draining lymph nodes, where they prime vaccine-specific T cells. The potency with which LVs activate CD8 T cell immunity has been attributed to the transduction of DCs at the immunization site and durable presentation of LV-encoded antigens. However, it is not known how LV-encoded antigens continue to be presented to T cells once directly transduced DCs have turned over. Here, we report that LV-encoded antigen is efficiently cross-presented by DCs in vitro. We have further exploited the temporal depletion of DCs in the murine CD11c.DTR (diphtheria toxin receptor) model to demonstrate that repopulating DCs that were absent at the time of immunization cross-present LV-encoded antigen to T cells in vivo. Indirect presentation of antigen from transduced cells by DCs is sufficient to prime functional effector T cells that control tumor growth. These data suggest that DCs cross-present immunogenic antigen from LV-transduced cells, thereby facilitating prolonged activation of T cells in the absence of circulating LV particles. These are findings that may impact on the future design of LV vaccination strategies.
重组慢病毒载体（LVs）是高效的疫苗载体，可在疾病模型中引发保护性T细胞免疫。树突状细胞（DCs）在疫苗接种部位摄取抗原，并迁移至引流淋巴结，在那里它们启动疫苗特异性T细胞。LVs激活CD8 T细胞免疫的效力归因于免疫部位DCs的转导以及LV编码抗原的持久呈递。然而，尚不清楚一旦直接转导的DCs更新后，LV编码的抗原如何继续呈递给T细胞。在此，我们报告LV编码的抗原在体外可被DCs有效交叉呈递。我们进一步利用小鼠CD11c.DTR（白喉毒素受体）模型中DCs的暂时耗竭，证明在免疫时不存在的重新填充的DCs在体内将LV编码的抗原交叉呈递给T细胞。DCs从转导细胞中间接呈递抗原足以启动控制肿瘤生长的功能性效应T细胞。这些数据表明，DCs交叉呈递来自LV转导细胞的免疫原性抗原，从而在没有循环LV颗粒的情况下促进T细胞的长期激活。这些发现可能会影响LV疫苗接种策略的未来设计。
