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

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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.