Quantitative approaches for profiling the T cell receptor repertoire in human tissues

The study of B and T cell receptor repertoires from high throughput sequencing is a recent development that allows for unprecedented resolution and quantification of the adaptive immune response. The immense diversity and long tailed distribution of these repertoires has up until now limited such studies to expanded clonal signatures or to analysis of imprecise signals with limited dynamic range collected by techniques such as radioactive and fluorescent labeling. This thesis presents a number of quantitative methods to characterize the repertoire and examine the questions of sequence diversity and inter-repertoire divergence of T cell repertoires. These approaches attempt to accurately parametrize the inherent distribution of T cell clones drawing from statistical tools derived from ecological literature and information theory. The methods presented are applied to T cell analyses of various tissue compartments of the human body, including peripheral blood mononucleocytes, thymic tissues, spleen, inguinal lymph nodes, lung lymph nodes and the brain. A number of applications are explored with strong implications for translational use in medicine. Novel insights are made into the mechanism of maintenance and compartmentalization of na{\"i}ve T cells from human donors of many different ages. Diversity and divergence of the tumor infiltrating sequence repertoire is measured in low grade gliomas and glioblastomas from cancer patients, and potential sequence based biomarkers are assessed for studying glioma phenotype progression. A careful investigation of the immune response to allogeneic stimulus reveals the effect of HLA on sequence sharing and diversity of the alloresponse, and quantifies for the first time using sequence data the fraction of T cells in a repertoire that are alloreactive. The use of repertoire sequencing and mathematical models within immunology is a new and emerging concept within the rapidly expanding field of systems immunology and will undoubtedly have a profound impact on the future of immunology research. It is hoped that the tools presented in this thesis will give insight into how to quantitatively explore the breadth and depth of the T cell receptor repertoire, and provide future directions for TCR repertoire analysis.