Collaborative Research: Understanding Generation, Maintenance, and Dynamics of Immune Diversity via Clone-Count Models

该项目将利用数学和计算方法来理解适应性免疫系统多样性的进化。表达不同细胞表面受体（或“克隆型”）的T细胞由胸腺产生，并允许生物体对广谱病原体做出反应。有多少不同的表面细胞受体和它们在T细胞池中的总数是决定生物体中和病原体能力的关键数量。研究结果有可能显着提高对免疫库如何随着感染和衰老而演变的理解，如何更准确地测量它，以及它如何受到胸腺移植等程序的影响。 作为研究的一部分，研究人员还将促进一系列涉及加州大学北岭分校和加州大学洛杉矶分校学生的教育活动，包括联合研讨会，学生演讲和暑期项目。两个代表计数克隆型，克隆计数和细胞计数，将进一步发展，以更好地衡量和量化适应性免疫系统。克隆计数描述由特定数量的细胞表示的T细胞克隆型的数量，而细胞计数量化每个克隆型内的细胞数量。T细胞群体和T细胞多样性的数学模型通常使用这两种表示之一，并且通常依赖于强生理假设。 大量的克隆型、每种克隆型的恒定出生和死亡、感染时某些克隆型的激活以及与疾病和衰老相关的胸腺输出的减缓都使得T细胞多样性的定量和预测具有挑战性。通过利用这两种表示之间的数学联系，研究人员将开发适用于更广泛生理条件下的免疫系统的T和B细胞成分的混合模型。 这些混合模型将是关键的扩展目前的模型，包括重要的生理过程，如克隆型增殖，细胞成熟和调节。最后，混合模型，包括确定性和随机性，将有助于更准确地确定一个有机体的免疫多样性，通过小的血液样本。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

The project will exploit mathematical and computational approaches to understand the evolution of the diversity of the adaptive immune system. T cells that express different cell surface receptors (or "clonotypes") are produced by the thymus and allow an organism to respond to a broad spectrum of pathogens. How many different surface cell receptors and their total numbers present in the T cell pool are critical quantities that determine an organism's ability to neutralize pathogens. Results of the research have the potential to significantly improve understanding of how the immune repertoire evolves with infections and aging, how it can be more accurately measured, and how it is affected by procedures such as thymic transplantation. As part of the research the investigators will also foster a series of educational activities involving Cal State-Northridge and UCLA students, including joint seminars, student presentations, and summer projects.Two representations of counting clonotypes, clone-counts and cell-counts, will be further developed to better measure and quantify the adaptive immune system. Clone-counts describe the number of T cell clonotypes represented by a specific number of cells while cell-counts quantify the number of cells within each clonotype. Mathematical models for T cell populations and T cell diversity typically use one of these two representations and often rely on strong physiological assumptions. The large number of clonotypes, the constant birth and death of each clonotype, the activation of certain clonotypes upon infection, and the slowing down of thymic output associated with disease and aging all render the quantification and prediction of T cell diversity challenging. By exploiting the mathematical connection between these two representations, the investigators will develop hybrid models of T and B cell components of the immune system applicable under a wider range of physiological conditions. These hybrid models will be pivotal in extending current models to include important physiological processes such as clonotype proliferation, cellular maturation, and regulation. Finally, hybrid models, both deterministic and stochastic, will facilitate more accurate determination of an organism's immune diversity through small blood samples.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.