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Abstract
T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self. High-throughput TCR sequencing (TCR-seq) involves the use of next generation sequencing platforms to generate large numbers of short DNA sequences covering key regions of the TCR coding sequence, which enables quantification of T-cell diversity at unprecedented resolution. TCR-seq studies have provided new insights into the healthy human T-cell repertoire, such as revised estimates of repertoire size and the understanding that TCR specificities are shared among individuals more frequently than previously anticipated. In the context of disease, TCR-seq has been instrumental in characterizing the recovery of the immune repertoire after hematopoietic stem cell transplantation, and the method has been used to develop biomarkers and diagnostics for various infectious and neoplastic diseases. However, T-cell repertoire sequencing is still in its infancy. It is expected that maturation of the field will involve the introduction of improved, standardized tools for data handling, deposition and statistical analysis, as well as the emergence of new and equivalently large-scale technologies for T-cell functional analysis and antigen discovery. In this review, we introduce this nascent field and TCR-seq methodology, we discuss recent insights into healthy and diseased TCR repertoires, and we examine the applications and challenges for TCR-seq in the clinic.
Highlights
T-cell antigen receptor (TCR) variability enables the cellular immune system to discriminate between self and non-self
Conclusions and future directions High-throughput sequencing applied to profiling TCR repertoires provides a new high-resolution view of cellular immunology, and has yielded new insights into the properties of normal T-cell repertoires in ordinary, healthy individuals, plus a view of T-cell repertoires affected by disease and/or modified by transplantation
TCR-pMHC engagement tends to be low affinity [59] compared with other biomolecular interactions such as antibody binding, and there is extensive cross-reactivity, whereby a given TCR can recognize many pMHC targets, and a given pMHC can be recognized by numerous TCRs [54,60]
Summary
High-throughput sequencing applied to profiling TCR repertoires provides a new high-resolution view of cellular immunology, and has yielded new insights into the properties of normal T-cell repertoires in ordinary, healthy individuals, plus a view of T-cell repertoires affected by disease and/or modified by transplantation. Given the personalized nature of immune repertoires, clinical applications of TCR-seq will require patient-specific approaches, and cost reduction will increasingly become a driving factor Another challenge is building data acquisition and analysis pipelines that are fast enough to provide actionable information in clinically relevant timeframes (often on the order of days), and sufficiently accurate for regulatory approval and for acceptance by clinicians and patients. Studies indicated that TCR diversity correlated with viral control, but more recently these findings have been countered with reports that public TCR sequences are more important and are a superior predictor of patient response to HIV infection These studies have been hampered by low sample sizes, heterogeneous patient populations and disease stages, as well as incomplete snapshots of the TCR repertoire due to the relatively low throughput methods employed - issues that may be ameliorated with TCR-seq. Competing interests The authors declare that they have no competing interests
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