T Cell Mechanosensing of Microscale Fibers

微型纤维的 T 细胞机械传感

• 批准号: 9917202
• 负责人: Lance C Kam
• 金额: $ 24.3万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-24 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917202
• 关键词: Actins; Address; Adoptive Immunotherapy; Affect; Antigen-Presenting Cells; Binding; Biocompatible Materials; CAR T cell therapy; CD28 gene; CD3 Antigens; Caliber; Cell Culture Techniques; Cell physiology; Cells; Cellular immunotherapy; Chemicals; Communication; Complex; Development; Dimensions; Disease; Elastomers; Electrospinning; Engineering; Environment; Excision; Fiber; Future; Generations; Geometry; Goals; Human; Image; Immunotherapy; Individual; Knowledge; Lead; Length; Ligands; Malignant Neoplasms; Mechanics; Microfabrication; Modulus; Molecular; Patients; Pharmaceutical Preparations; Pharmacology; Play; Production; Research; Role; Series; Signal Transduction; Structure; Surface; System; T cell response; T-Cell Activation; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Tissue Engineering; base; cancer therapy; cell growth; cost; design; experimental study; extracellular; fiber cell; improved; insight; interest; mechanical force; mechanical properties; mechanotransduction; polymerization; public health relevance; response; tool

Abstract Mechanical forces play critical roles in communication between T cells and Antigen Presenting Cells (APCs). Previous studies from our research group demonstrated that T cells can sense and respond to the mechanical rigidity of an activating substrate presenting ligands to TCR/CD3 and CD28, essentially an engineered APC. This discovery led to new systems for improving production of human T cells for cellular immunotherapy. In particular, a system based on soft elastomer fibers produced more cells per round of expansion than a rigid counterpart, and also rescued expansion of cells from individuals being treated for cancer. However, these previous experiments also suggested that the underlying mechanosensing response is dependent on not only the bulk modulus of the material but also its structure at scales comparable to or even larger than that of the attached cells. The overall purpose of this exploratory / developmental project is to identify what features of this mesh platform, such as fiber diameter and/or span length influence T cell mechanosensing. This will be approached in two complementary Specific Aims. In the first, a strategic set of fiber geometries that independently vary the multiple parameters of interest will be created by further developing electrospinning and microfabrication of elastomers. Comparison of multiple T cell responses to these fibers will be used to separate and quantify the effects of each parameter. The second Specific Aim focuses on the adherent T cell, characterizing the internal assemblies that lead to force generation. Together, these studies will address the current gap in knowledge of how T cells mechanically interact with topographically complex substrates, providing both insights into how these cells recognize and attack target cells and strategies to improve the emerging cellular immunotherapy market.

抽象的 机械力在 T 细胞和抗原呈递细胞之间的通讯中发挥着关键作用 （装甲运兵车）。我们研究小组之前的研究表明，T 细胞可以感知并响应 呈递 TCR/CD3 和 CD28 配体的激活底物的机械刚性，本质上是 工程APC。这一发现催生了改善人类 T 细胞生产的新系统 免疫疗法。特别是，基于软弹性纤维的系统每轮产生更多的细胞 比刚性对应物的扩增，并且还拯救了接受治疗的个体的细胞扩增 癌症。然而，之前的这些实验也表明潜在的机械传感响应是 不仅取决于材料的体积模量，还取决于其在相当甚至尺度上的结构 比贴壁细胞大。这个探索性/开发项目的总体目的是 确定该网状平台的哪些特征（例如纤维直径和/或跨度长度）会影响 T 细胞 机械传感。这将通过两个互补的具体目标来实现。首先，制定一套战略 独立改变多个感兴趣参数的纤维几何形状将通过进一步创建 开发弹性体的静电纺丝和微加工。多种 T 细胞反应的比较 这些纤维将用于分离和量化每个参数的影响。第二个具体目标 重点关注贴壁 T 细胞，表征导致力产生的内部组件。一起， 这些研究将解决目前关于 T 细胞如何与细胞机械相互作用的知识空白。 地形复杂的基质，提供了关于这些细胞如何识别和攻击目标的见解 细胞和改善新兴细胞免疫治疗市场的策略。