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了解适应性免疫系统多样性的进化。胸腺产生表达不同细胞表面受体(或“克隆型”)的T细胞，使生物体对广泛的病原体产生反应。T细胞池中存在多少不同的表面细胞受体及其总数是决定生物体中和病原体能力的关键数量。研究结果有可能显著提高对免疫谱系如何随着感染和衰老而演变的理解，如何更准确地测量免疫谱系，以及胸腺移植等程序如何影响免疫谱系。作为研究的一部分，研究人员还将促进一系列涉及加州州立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、学生陈述和暑期项目。将进一步开发计数克隆类型、克隆计数和细胞计数的两种表示法，以更好地测量和量化适应性免疫系统。克隆计数描述了由特定数量的细胞代表的T细胞克隆类型的数量，而细胞计数则量化了每个克隆类型中的细胞数量。T细胞种群和T细胞多样性的数学模型通常使用这两种表示法中的一种，并且通常依赖于强烈的生理假设。大量的克隆型，每个克隆型的不断出生和死亡，某些克隆型在感染时的激活，以及与疾病和衰老相关的胸腺输出的减慢，这些都给T细胞多样性的量化和预测带来了挑战。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的生理条件的免疫系统T细胞和B细胞成分的混合模型。这些杂交模型将在扩展现有模型以包括克隆增殖、细胞成熟和调节等重要生理过程方面发挥关键作用。最后，混合模型，包括确定性和随机性，将有助于通过少量血液样本更准确地确定有机体的免疫多样性。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.