Structural biophysics and molecular design in cellular immunity

 描述(申请人提供)：αβT细胞受体(TCR)识别主要组织相容性复合体蛋白(PMHC)呈递的多肽抗原是细胞免疫的基石，定义特异性并启动导致T细胞介导的免疫反应的信号。尽管TCR-pMHC相互作用的数据在过去十年中显著增加，但我们仍然对T细胞和TCR如何实现其非凡的识别特性知之甚少。尽管如此，TCR和T细胞表位在免疫治疗中的应用继续快速增长，特别是在癌症治疗中。虽然免疫治疗取得了成功，但也出现了并发症和挫折。人们普遍认为，需要对TCR/T细胞识别有更好的了解，这样的治疗才能发挥其潜力。这项建议描述了一项雄心勃勃、紧密集成的研究，它融合了蛋白质生物物理学、结构生物学、计算和免疫学，以了解TCR识别、信号和免疫调节。它还描述了通过将TCR识别方面的进展整合到计算设计和建模工作中来设计和改进基于免疫的疗法的一般策略的发展，反之亦然。重点包括：1)确定TCR-pMHC结合是如何由进化和非进化力量形成的；2)了解T细胞识别中潜在的特异性和交叉反应的不同机制；3)确定分子运动在TCR触发中的作用，包括完整TCR/CD3复合体的结构和动力学性质；4)学习如何设计具有改进的分子识别特性的TCR，强调抗原特异性和仔细调节而不是简单地增强亲和力的能力；5)开发高通量模拟TCR交叉反应和MHC蛋白质中新抗原的结构/动力学性质的计算技术；以及6)了解多肽如何改变MHC的性质，而不是那些可以从静态结构中确定的性质，以及这种调制如何影响细胞免疫。

 DESCRIPTION (provided by applicant): αβ T cell receptor (TCR) recognition of peptide antigens presented by major histocompatibility complex proteins (pMHC) is a cornerstone of cellular immunity, defining specificity and initiating the signaling that leads to T cell-mediated immune responses. Although data for TCR-pMHC interactions has increased significantly over the past decade, we still have a poor understanding of how T cells and TCRs achieve their extraordinary recognition properties. Nonetheless, there continues to be rapid growth in the use of TCRs and T cell epitopes for immunotherapy, particularly for cancer. While there have been immunotherapy successes, there have also been complications and setbacks. It is widely accepted that an improved understanding of TCR/T cell recognition is needed for such therapies to reach their potential. This proposal describes an ambitious, tightly integrated study that blends protein biophysics, structural biology, computation, and immunology to understand TCR recognition, signaling, and immune modulation. It also describes the development of general strategies for designing and improving immune-based therapeutics by incorporating advances in TCR recognition into efforts in computational design and modeling, and vice versa. Priorities include 1) determining how TCR-pMHC binding is shaped by evolutionary and non-evolutionary forces; 2) understanding the varied mechanisms underlying specificity and cross-reactivity in T cell recognition; 3) determining the role of molecular motion in TCR triggering, including the structural and dynamical properties of intact TCR/CD3 complexes; 4) learning how to design TCRs with improved molecular recognition properties, emphasizing antigen specificity and the ability to carefully modulate rather than simply enhance affinity; 5) developing computational techniques for high throughput modeling of TCR cross-reactivity and the structural/dynamical properties of neo-antigens in MHC proteins; and 6) learning how peptides alter MHC properties beyond those ascertainable from static structures and how this modulation impacts cellular immunity.