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High-throughput and single-cell T cell receptor sequencing technologies

Abstract

T cells express T cell receptors (TCRs) composed of somatically recombined TCRα and TCRβ chains, which mediate recognition of major histocompatibility complex (MHC)–antigen complexes and drive the antigen-specific adaptive immune response to pathogens and cancer. The TCR repertoire in each individual is highly diverse, which allows for recognition of a wide array of foreign antigens, but also presents a challenge in analyzing this response using conventional methods. Recent studies have developed high-throughput sequencing technologies to identify TCR sequences, analyze their antigen specificities using experimental and computational tools, and pair TCRs with transcriptional and epigenetic cell state phenotypes in single cells. In this Review, we highlight these technological advances and describe how they have been applied to discover fundamental insights into T cell-mediated immunity.

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Fig. 1: Characterization of T cell dynamics using multiomic TCR sequencing approaches.
Fig. 2: Overview of single-cell TCR sequencing approaches.
Fig. 3: Schematic of paired scRNA-seq and TCR sequencing methods.
Fig. 4: Overview of single-cell methods for linking TCR sequence to antigen specificity.

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Acknowledgements

This work was supported by National Institutes of Health grants K08CA230188 (A.T.S.) and 5T32AI007290 (J.A.P.), the Parker Institute for Cancer Immunotherapy, a Technology Impact Award from the Cancer Research Institute and a Career Award for Medical Scientists from the Burroughs Wellcome Fund (A.T.S.).

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Correspondence to Ansuman T. Satpathy.

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A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from 10x Genomics, Arsenal Biosciences and Allogene Therapeutics.

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Peer review information Nature Methods thanks Benny Chain, Encarnita Mariotti-Ferrandiz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Madhura Mukhopadhyay was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Pai, J.A., Satpathy, A.T. High-throughput and single-cell T cell receptor sequencing technologies. Nat Methods 18, 881–892 (2021). https://doi.org/10.1038/s41592-021-01201-8

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