NEXT-GENERATION ANALYSES OF T CELL RECEPTOR REPERTOIRES

A deep understanding of the T cell receptor repertoire is paramount to a thorough understanding of the adaptive immune system and the development of therapeutics that harness its power. Due to the vast diversity of the immune repertoire, detailed and accurate characterization can pose an immense challenge. This work uses several high-throughput, high-dimensional assays and analyses that aim at overcoming these challenges. Specifically, T cell specificity, phenotype, function, and kinetics are linked through deep analyses of T cell receptor repertoires through time and immune perturbations from HIV infection to SARS-CoV-2 infection and vaccination. Through this work, several novel biological and biophysical findings are addressed including 1) the presence and phenotypic characterization of a follicular helper T cell (TFH) population that is inflated during HIV infection, 2) the characterization of a delayed T cell response intrinsic to COVID-19, 3) the prediction and characterization of specific epitopes that may discriminate non- severe from severe COVID-19 patients, and 4) the depiction of a novel mechanism, centered around immunodominance, TCR diversity, and TCR promiscuity, utilized by the adaptive immune system to resist antigenic drift. The implications of this work reach far beyond specific disease contexts and can be applied generally to both the adaptive immune system and the manytherapeutics that utilize it.