Stochastic modelling of cellular immune responses: crossing the theoretical-experimental divide

适应性细胞免疫系统通过T细胞抗原受体（TCR）识别致病性抗原，TCR通过主要组织相容性复合体（MHC）蛋白与抗原呈递细胞（APCs）表面显示的肽抗原相互作用。免疫系统包含数百万个不同的TCR分子，这些分子是由编码TCR分子与肽- mhc （pMHC）复合物相互作用区域的基因片段的随机重排形成的。每个T细胞表达一种特定的TCR物种或克隆型，这是T细胞及其所属克隆所特有的。T细胞与APCs的相互作用是控制自身耐受性和效应功能的关键事件。了解TCR- pmhc相互作用和TCR触发是找到控制T细胞激活的合适靶点的先决条件。本提案旨在通过利用现有的数学和实验模型，为T细胞免疫学提供一种系统生物学方法：(1)了解T细胞受体（TCR-CD3）触发、TCR聚集和CD3亚基细胞质尾部构象变化；(2)了解中央耐受诱导的T细胞库结构如何与胸腺自身抗原呈递统计相关；(3)了解T细胞数量如何被稳态调节以维持T细胞库的大小和多样性。本提案的总体目标是提供适应免疫学定量和系统生物学的观点。这将通过利用现有的数学模型和实验数据来实现，以便(i)用初步的实验数据测试现有的数学模型，（ii）改进这些数学模型，（iii）提出新的实验，（iv）产生新的实验可测试的假设。Molina-Paris博士的目标是利用随机方法模拟适应性免疫反应，并与实验免疫学家密切合作。拟议的研究项目属于BBSRC的优先事项和使命：系统生物学和生物学的数学工具。因此，总的来说，BBSRC研究发展奖学金对申请人、BBSRC的职责范围和英国科学来说都是及时的。该奖学金不仅将为研究员的研究开辟重要的新方向，而且将提供跨学科的维度，并为她的研究、她的小组成员和I2M网络成员带来新的实验技术和方法。此外，现在开展这项工作也是及时的，因为“免疫学仍然是粗略的经验主义”。

The adaptive cellular immune system recognises pathogenic antigens by means of the T~cell antigen receptor (TCR), which interacts with peptide antigens displayed on the surface of antigen presenting cells (APCs) by major histocompatibility complex (MHC) proteins. The immune system contains millions of distinct TCR molecules, formed by random rearrangement of the gene segments encoding the region of the TCR molecule that interacts with the peptide-MHC (pMHC) complex. Each T~cell expresses one specific TCR species or clonotype, unique to the T~cell and the clone to which it belongs. The interaction of T~cells with APCs is a key event in the control of both self-tolerance and effector function. Understanding TCR-pMHC interactions and TCR triggering is the pre-requisite to finding suitable targets that control T~cell activation. This proposal aims to provide a systems biology approach to T~cell immunology by making use of both current mathematical and experimental models to: (1) understand T~cell receptor (TCR-CD3) triggering, TCR clustering and conformational changes at the cytoplasmic tails of the CD3 subunits, (2) understand how the T~cell repertoire structure induced by central tolerance is related to thymic self-antigen presentation statistics, and (3) understand how T~cell numbers are homeostatically regulated to maintain both the size and diversity of the T~cell repertoire. The overall goal of this proposal is to provide adaptive immunology with a quantitative and systems biology perspective. This will be achieved by making use of both current mathematical models and experimental data, in order to (i) test existing mathematical models with preliminary experimental data, (ii) refine those mathematical models, (iii) suggest new experiments and (iv) generate new experimentally testable hypothesis. Dr. Molina-Paris aims to model adaptive immune responses using stochastic methods and working closely with experimental immunologists. The proposed research project falls within the priorities and mission of BBSRC: systems biology and mathematical tools for biology. Thus, the BBSRC Research Development Fellowship is both timely to the applicant and to the BBSRC remit and UK science, in general. This Fellowship will not only open up significant new directions in the fellow's research but will also give an inter-disciplinary dimension and bring new experimental techniques and methodologies to her research, the members of her group and the members of the I2M network. Furthermore, it is also timely that this work should be carried out now as 'immunology remains crassly empirical'.