Biomimetic Matrix for Ex Vivo and In Vivo Activation of T Cells

项目总结 这项研究的目的是设计一种人工T细胞刺激基质(ATM)，它呈现抗原特异性 和细胞特异的生化和生物物理线索来控制T细胞的表型和改善其功能 仿生背景，捕捉淋巴(LN)的关键生化和生物物理特征。LN提供了 关键微环境，协调抗原特异信号的呈现格式和动态 精确和可控的方式，导致T细胞的激活、扩增和成熟。当前可用的T细胞 然而，在携带抗原呈递复合体和共刺激线索的同时刺激基质，缺乏 LN中T细胞刺激微环境所固有的足够支持线索。我们将设计和 描述集成了三个关键T细胞刺激信号的ATM的特征：抗原特异性(信号1)、共刺激 (信号2)和细胞因子(信号3)，以及细胞外基质(ECM)分子和可调生物物理 由抗原提呈细胞(APC)和LN的特性启发而来的特性。我们将检验这一假设 在T细胞刺激期间在这样的仿生环境中共同呈现APC信号提示将导致功能性 具有受控表型和效力的T细胞。以及揭示所有信号信号如何协同作用的机制 活化和极化T细胞。在具体目标1中，我们将确定ATM的关键矩阵属性 透明质酸水凝胶和透明质酸纳米纤维复合材料制备的ATM对CD8+T细胞的激活作用 矩阵。在具体目标2中，我们将定义影响最佳信令提示及其呈现配置 在ATM上的CD4+T细胞的激活和极化；并展示了ATM刺激的和 过继转移的抗原特异性CD4+T细胞。在特定的目标3中，我们将使用ATM微粒来协同刺激 CD_8~+和CD_4~+T细胞及其联合治疗的疗效 一种肿瘤免疫治疗的小鼠模型。如果成功，这项研究将产生第一套工程化ATM 提供强大的抗原特异性CD8+和CD4+T细胞的刺激，承诺改善治疗结果； 进一步丰富了我们对刺激、极化等信号传递线索的设计原理和机制的理解 和T细胞的激活。

PROJECT SUMMARY The objective of this study is to engineer an artificial T cell-stimulating matrix (aTM) that presents antigen-specific and cell-specific biochemical and biophysical cues to control phenotype and improve functional profiles of T cells in a biomimetic context that captures key biochemical and biophysical features of the lymph node (LN). LN provides the critical microenvironment that orchestrates the presentation format and dynamics of the antigen-specific signals in a precise and controlled manner that leads to T cell activation, expansion, and maturation. Currently available T cell stimulating matrices while carrying the antigen-presentation complexes and co-stimulating cues, however, lacks adequate supporting cues inherent to the T cell stimulating microenvironment in the LN. We will design and characterize an aTM that integrates the three key T-cell stimulating signals: antigen-specific (Signal 1), co-stimulatory (Signal 2), and cytokines (Signal 3), together with extracellular matrix (ECM) molecules and tunable biophysical properties inspired by the properties of both antigen-presenting cells (APCs) and the LN. We will test the hypothesis that co-presenting the APC signal cues in such a biomimetic context during T cell stimulation will result in functional T cells with controlled phenotypic profiles and potency. and mechanism revealing how all signaling cues synergize to active and polarize T cells. In Specific Aim 1, we will determine key matrix properties of the aTM that mediate robust CD8+ T cell activation using aTMs prepared from hyaluronic acid (HA) hydrogel and HA-nanofiber composite (NHC) matrix. In Specific Aim 2, we will define optimal signaling cues and their presentation configuration that influence CD4+ T cell activation and polarization on aTM; and demonstrate persistence and functions of aTM-stimulated and adoptively transferred antigen-specific CD4+ T cells. In Specific Aim 3, we will use aTM microparticles to co-stimulate CD8+ and CD4+ T cells and evaluate therapeutic benefits of a combination treatment with CD4+ and CD8+ T cells in a cancer immunotherapy mouse model. If successful, this study will result in the first set of engineered aTM that delivers robust stimulation of antigen-specific CD8+ and CD4+ T cells that promise improved therapeutic outcomes; and further enrich our understandings of design principles and mechanism of signaling cues in stimulation, polarization, and activation of T cells.