Structural biophysics and molecular design in cellular immunity

 描述（由申请方提供）：αβ T细胞受体（TCR）对主要组织相容性复合体蛋白（pMHC）呈递的肽抗原的识别是细胞免疫的基石，定义特异性并启动导致T细胞介导的免疫应答的信号传导。尽管在过去的十年中，TCR-pMHC相互作用的数据显著增加，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，使用TCR和T细胞表位进行免疫治疗（特别是癌症治疗）的数量仍在快速增长。虽然免疫疗法取得了成功，但也出现了并发症和挫折。人们普遍认为，需要对TCR/T细胞识别的更好理解，这样的疗法才能发挥其潜力。该提案描述了一项雄心勃勃的，紧密集成的研究，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，信号传导和免疫调节。它还描述了通过将TCR识别的进展纳入计算设计和建模的努力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。优先事项包括1）确定TCR-pMHC结合如何由进化和非进化力量形成; 2）理解T细胞识别中特异性和交叉反应性的不同机制; 3）确定分子运动在TCR触发中的作用，包括完整TCR/CD 3复合物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）开发用于TCR交叉反应性和MHC蛋白中新抗原的结构/动力学性质的高通量建模的计算技术;和6）了解肽如何改变MHC性质，而不是从静态结构中确定的性质，以及这种调节如何影响细胞免疫。

 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.