The specificity of antigen recognition by a T cell or B cell is determined by its unique T cell receptor (TCR) or B cell receptor (BCR), each consisting of two, paired polypeptide chains (alpha and beta, or heavy and light, respectively). An immense diversity of receptors is created during T cell and B cell development through a process of gene recombination. Previously, this diversity has been studied by extracting RNA from large numbers of cells, amplifying the alpha and beta chain (or heavy

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... nd light chain) transcripts, and then deep sequencing. However, through this process, information on correct chain pairing is lost. In this thesis, I present a high-throughput approach for maintaining paired-chain information in next-generation sequencing libraries. Briefly, a bulk cell population is divided into a number of sub-populations, and TCR or BCR transcripts are independently amplified; chains are considered paired if they co-occur in more sub-populations than expected by random chance. Fundamental to this approach is a reliable, sensitive library preparation chemistry in which a sub-population specific index can be incorporated. Such a chemistry was validated on primary human CD8⁺ T cells. This approach for antigen receptor chain pairing will enable in-depth studies of immune dynamics, tracking of disease progression, and personalized immunotherapeutics.