Immune repertoire sequencing with application to infectious disease

Abstract

B and T lymphocytes are the cellular effectors of the adaptive immune system and perform the learning and recall functions that are the basis of immunological memory. Immunoglobulin and T cell receptors enable the immune system to recognize an enormous set of exogenous and endogenous antigens. The vast majority of B and T cell clones possess a single unique heterodimeric receptor with a highly diverse binding domain generated through ordered somatic gene rearrangements known as V(D)J recombination. The combination of different (Variable, Diversity and Joining) gene segments, insertion and deletion of non-templated nucleotides at the junctions between segments and pairing of heavy and light chains control the specificity of recognition. As a result, the diversity of B and T cell receptors in the body determine an individual's ability to respond to new and previously seen antigens. In this work, I present a database of B cell receptor sequences that unites experimental and computational techniques to accurately estimate the richness of the naïve and memory B cell repertoires. I also present two studies exploring the diversity of the T cell repertoire in acute and chronic viral infections. To study the diversity of the T cell repertoire in response to an acute infection, I combine live-attenuated yellow fever virus vaccination and T cell repertoire sequencing to identify and track vaccine responsive clones longitudinally. Lastly, I explore the hypothesis that chronic cytomegalovirus infection in the elderly compromises immune function by reducing CD8+ T cell repertoire diversity. Together these studies further our understanding of the relationship between immune repertoire diversity and immune function.