Integrin-Assisted T-Cell Activation on Nanostructured Hydrogels,Nano Letters

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Integrin-Assisted T-Cell Activation on Nanostructured Hydrogels
Nano Letters ( IF 9.6 ) Pub Date : 2017-09-06 00:00:00 , DOI: 10.1021/acs.nanolett.7b02636
Judith Guasch _{1,

2,

3,

4} , Christine A. Muth _{3,

4} , Jennifer Diemer _{3,

4} , Hossein Riahinezhad _{3,

4} , Joachim P. Spatz _{3,

4}

Affiliation

Adoptive cell therapy (ACT) has shown very promising results as treatment for cancer in a few clinical trials, such as the complete remissions of otherwise terminal leukemia patients. Nevertheless, the introduction of ACT into clinics requires overcoming not only medical but also technical challenges, such as the ex vivo expansion of large amounts of specific T-cells. Nanostructured surfaces represent a novel T-cell stimulation technique that enables us to fine-tune the density and orientation of activating molecules presented to the cells. In this work, we studied the influence of integrin-mediated cell-adhesion on T-cell activation, proliferation, and differentiation using nanostructured surfaces, which provide a well-defined system at the nanoscale compared with standard cultures. Specifically, we synthesized a polymeric polyethylene glycol (PEG) hydrogel cross-linked with two fibronectin-derived peptides, cyclic Arg-Gly-Asp (cRGD) and cyclic Leu-Asp-Val (cLDV), that are known to activate different integrins. Moreover, the hydrogels were decorated with a quasi-hexagonal array of gold nanoparticles (AuNPs) functionalized with the activating antibody CD3 to initiate T-cell activation. Both cLDV and cRGD hydrogels showed higher T-cell activation (CD69 expression and IL-2 secretion) than nonfunctionalized PEG hydrogels. However, only the cRGD hydrogels clearly supported proliferation giving a higher proportion of cells with memory (CD4⁺CD45RO⁺) than naı̈ve (CD4⁺CD45RA⁺) phenotypes when interparticle distances smaller than 150 nm were used. Thus, T-cell proliferation can be enhanced by the activation of integrins through the RGD sequence.

中文翻译：

整合素辅助的T细胞在纳米结构水凝胶上的活化

在一些临床试验中，过继性细胞疗法（ACT）已显示出非常有希望的结果作为治疗癌症的方法，例如完全治愈了其他晚期白血病患者。然而，将ACT引入临床不仅需要克服医学上的挑战，还需要克服技术上的挑战，例如体外大量扩增特定的T细胞。纳米结构表面代表了一种新颖的T细胞刺激技术，使我们能够微调呈现给细胞的激活分子的密度和方向。在这项工作中，我们研究了整合素介导的细胞粘附对使用纳米结构表面的T细胞活化，增殖和分化的影响，与标准培养相比，纳米结构提供了一个定义明确的系统。具体来说，我们合成了与两个纤连蛋白衍生肽（环状Arg-Gly-Asp（cRGD）和环状Leu-Asp-Val（cLDV））交联的聚合物聚乙二醇（PEG）水凝胶，已知它们可以激活不同的整合素。此外，水凝胶用被激活抗体CD3官能化以启动T细胞激活的金纳米颗粒（AuNPs）的准六边形阵列修饰。cLDV和cRGD水凝胶均显示出比未官能化的PEG水凝胶更高的T细胞活化（CD69表达和IL-2分泌）。然而，只有cRGD水凝胶清楚地支持增殖，从而赋予更多具有记忆力的细胞（CD4 水凝胶用准六边形阵列的金纳米粒子（AuNPs）修饰，金纳米粒子用激活抗体CD3进行功能化以启动T细胞激活。cLDV和cRGD水凝胶均显示出比未官能化的PEG水凝胶更高的T细胞活化（CD69表达和IL-2分泌）。然而，只有cRGD水凝胶清楚地支持增殖，从而赋予更多具有记忆力的细胞（CD4 水凝胶用准六边形阵列的金纳米粒子（AuNPs）修饰，金纳米粒子用激活抗体CD3进行功能化以启动T细胞激活。cLDV和cRGD水凝胶均显示出比未官能化的PEG水凝胶更高的T细胞活化（CD69表达和IL-2分泌）。然而，只有cRGD水凝胶清楚地支持增殖，从而赋予更多具有记忆力的细胞（CD4⁺ CD45RO ⁺）比幼稚（CD4 ⁺ CD45RA ⁺）表型时间距离小于150纳米使用。因此，可以通过RGD序列激活整联蛋白来增强T细胞增殖。

更新日期：2017-09-06

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