![]() Successful interrogation of a broad repertoire of immune receptors for therapeutically useful clones depends on analysis techniques that are of sufficient throughput to insure adequate sampling from a polyclonal population but which retain the sensitivity needed to find rare cells of desired specificity or functional capacity within heterogenous material such as blood or tissue biopsies. Nesterenko et al., in PNAS, report on a powerful advance in efforts to enable the discovery of such useful immune receptors ( 3). Given this remarkable heterogeneity, identification of TCRs capable of recognizing specific antigens from pathogens, tumors, or normal self continues to be an area of active interest for both basic and applied immunology, with the latter effort holding clear therapeutic implications for TCR engineering of T cells for adoptiveimmunotherapy in cancer and autoimmunity ( 1, 2). Although there are a finite number of gene segments encoding the distinct variable (V), diversity (D), joining (J), and constant (C) that comprise the alpha and beta TCR chains, gene rearrangement and template-independent nucleotide addition to the final gene structure insure that the number of distinct TCRs that can be encoded far exceeds the number of clonal T cells present within the host. A defining feature of T cells is found in the specificity and functionality of the clonal antigen receptor (T cell receptor ), a heterodimeric surface protein that allows recognition of the set of peptide/major histocompatibility complexes (MHC) that can serve as activating ligands. ![]() T lymphocytes, for example, comprise a range of subsets that can be distinguished by specific phenotypic and activation surface markers that broadly connote their class and function, but which fail to resolve the specific gene expression patterns that are essential to understanding the contributions made by individual clones to the induction and maintenance of immunity. ![]() This feature, though central to its ability to respond to diverse and dynamic antigenic challenges, has complicated high-resolution single-cell analysis, due to the paucity of features by which an individual clonal lymphocyte lineage can be known. The adaptive arm of the immune system is perhaps unique among complex organ systems in the vast heterogeneity of its constituent cellular components.
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