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 透明质酸水凝胶和纳米纤维复合材料制备的ATM卡对CD8T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 CD4T细胞在ATM上的激活和极化；并展示ATM刺激和 过继转移的抗原特异性CD4T细胞。在特定的目标3中，我们将使用ATM微粒来协同刺激 CD8和CD8T细胞联合治疗的疗效评价 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CD4T细胞刺激，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.