Wengerter Brian C, Katakowski Joseph A, Rosenberg Jacob M, Park Chae Gyu, Almo Steven C, Palliser Deborah, Levy Matthew
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Mol Ther. 2014 Jul;22(7):1375-1387. doi: 10.1038/mt.2014.51. Epub 2014 Mar 31.
Effective therapeutic vaccines often require activation of T cell-mediated immunity. Robust T cell activation, including CD8 T cell responses, can be achieved using antibodies or antibody fragments to direct antigens of interest to professional antigen presenting cells. This approach represents an important advance in enhancing vaccine efficacy. Nucleic acid aptamers present a promising alternative to protein-based targeting approaches. We have selected aptamers that specifically bind the murine receptor, DEC205, a C-type lectin expressed predominantly on the surface of CD8α(+) dendritic cells (DCs) that has been shown to be efficient at facilitating antigen crosspresentation and subsequent CD8(+) T cell activation. Using a minimized aptamer conjugated to the model antigen ovalbumin (OVA), DEC205-targeted antigen crosspresentation was verified in vitro and in vivo by proliferation and cytokine production by primary murine CD8(+) T cells expressing a T cell receptor specific for the major histocompatibility complex (MHC) I-restricted OVA257-264 peptide SIINFEKL. Compared with a nonspecific ribonucleic acid (RNA) of similar length, DEC205 aptamer-OVA-mediated antigen delivery stimulated strong proliferation and production of interferon (IFN)-γ and interleukin (IL)-2. The immune responses elicited by aptamer-OVA conjugates were sufficient to inhibit the growth of established OVA-expressing B16 tumor cells. Our results demonstrate a new application of aptamer technology for the development of effective T cell-mediated vaccines.
有效的治疗性疫苗通常需要激活T细胞介导的免疫反应。使用抗体或抗体片段将感兴趣的抗原导向专业抗原呈递细胞，可实现包括CD8 T细胞反应在内的强大T细胞激活。这种方法代表了提高疫苗效力方面的一项重要进展。核酸适配体是基于蛋白质的靶向方法的一种有前景的替代方案。我们筛选出了能特异性结合小鼠受体DEC205的适配体，DEC205是一种C型凝集素，主要表达于CD8α(+)树突状细胞（DC）表面，已证明其在促进抗原交叉呈递及随后的CD8(+) T细胞激活方面效率很高。通过将最小化的适配体与模型抗原卵清蛋白（OVA）偶联，利用表达对主要组织相容性复合体（MHC）I类限制性OVA257 - 264肽SIINFEKL具有特异性的T细胞受体的原代小鼠CD8(+) T细胞的增殖和细胞因子产生，在体外和体内验证了靶向DEC205的抗原交叉呈递。与长度相似的非特异性核糖核酸（RNA）相比，DEC205适配体 - OVA介导的抗原递送刺激了强烈的增殖以及干扰素（IFN）-γ和白细胞介素（IL）-2的产生。适配体 - OVA偶联物引发的免疫反应足以抑制已建立的表达OVA的B16肿瘤细胞的生长。我们的结果证明了适配体技术在开发有效的T细胞介导疫苗方面的新应用。
