Hong Enping, Usiskin Ilana M, Bergamaschi Cristina, Hanlon Douglas J, Edelson Richard L, Justesen Sune, Pavlakis George N, Flavell Richard A, Fahmy Tarek M
From the Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06511.
the Vaccine Branch, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, and.
J Biol Chem. 2016 Apr 22;291(17):8931-50. doi: 10.1074/jbc.M115.695304. Epub 2015 Dec 30.
Here we report a "configuration-dependent" mechanism of action for IL-15:IL-15Rα (heterodimeric IL-15 or hetIL-15) where the manner by which IL-15:IL-15Rα molecules are presented to target cells significantly affects its function as a vaccine adjuvant. Although the cellular mechanism of IL-15 trans-presentation via IL-15Rα and its importance for IL-15 function have been described, the full effect of the IL-15:IL-15Rα configuration on responding cells is not yet known. We found that trans-presenting IL-15:IL-15Rα in a multivalent fashion on the surface of antigen-encapsulating nanoparticles enhanced the ability of nanoparticle-treated dendritic cells (DCs) to stimulate antigen-specific CD8(+) T cell responses. Localization of multivalent IL-15:IL-15Rα and encapsulated antigen to the same DC led to maximal T cell responses. Strikingly, DCs incubated with IL-15:IL-15Rα-coated nanoparticles displayed higher levels of functional IL-15 on the cell surface, implicating a mechanism for nanoparticle-mediated transfer of IL-15 to the DC surface. Using artificial antigen-presenting cells to highlight the effect of IL-15 configuration on DCs, we showed that artificial antigen-presenting cells presenting IL-15:IL-15Rα increased the sensitivity and magnitude of the T cell response, whereas IL-2 enhanced the T cell response only when delivered in a paracrine fashion. Therefore, the mode of cytokine presentation (configuration) is important for optimal immune responses. We tested the effect of configuration dependence in an aggressive model of murine melanoma and demonstrated significantly delayed tumor progression induced by IL-15:IL-15Rα-coated nanoparticles in comparison with monovalent IL-15:IL-15Rα. The novel mechanism of IL-15 transfer to the surface of antigen-processing DCs may explain the enhanced potency of IL-15:IL-15Rα-coated nanoparticles for antigen delivery.
在此，我们报告了白细胞介素-15：白细胞介素-15受体α（异二聚体白细胞介素-15或hetIL-15）的一种“构型依赖性”作用机制，即白细胞介素-15：白细胞介素-15受体α分子呈递给靶细胞的方式会显著影响其作为疫苗佐剂的功能。尽管已经描述了白细胞介素-15通过白细胞介素-15受体α进行反式呈递的细胞机制及其对白细胞介素-15功能的重要性，但白细胞介素-15：白细胞介素-15受体α构型对反应细胞的全面影响尚不清楚。我们发现，以多价形式在包裹抗原的纳米颗粒表面反式呈递白细胞介素-15：白细胞介素-15受体α可增强经纳米颗粒处理的树突状细胞（DCs）刺激抗原特异性CD8(+) T细胞反应的能力。多价白细胞介素-15：白细胞介素-15受体α和包裹的抗原定位于同一DC可导致最大的T细胞反应。令人惊讶的是，与用白细胞介素-15：白细胞介素-15受体α包被的纳米颗粒孵育的DCs在细胞表面显示出更高水平的功能性白细胞介素-15，这暗示了纳米颗粒介导的白细胞介素-15转移至DC表面的一种机制。使用人工抗原呈递细胞来突出白细胞介素-15构型对DCs的影响，我们表明呈递白细胞介素-15：白细胞介素-15受体α的人工抗原呈递细胞增加了T细胞反应的敏感性和强度，而白细胞介素-2仅以旁分泌方式递送时才增强T细胞反应。因此，细胞因子呈递模式（构型）对于最佳免疫反应很重要。我们在侵袭性小鼠黑色素瘤模型中测试了构型依赖性的影响，并证明与单价白细胞介素-15：白细胞介素-15受体α相比，用白细胞介素-15：白细胞介素-15受体α包被的纳米颗粒可显著延迟肿瘤进展。白细胞介素-15转移至抗原处理DC表面的新机制可能解释了用白细胞介素-15：白细胞介素-15受体α包被的纳米颗粒在抗原递送方面增强的效力。
