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Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells

Nature Biotechnology volume 32, pages 149–157 (2014)Cite this article

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Abstract

Adaptive immune responses often begin with the formation of a molecular complex between a T-cell receptor (TCR) and a peptide antigen bound to a major histocompatibility complex (MHC) molecule. These complexes are highly variable, however, due to the polymorphism of MHC genes, the random, inexact recombination of TCR gene segments, and the vast array of possible self and pathogen peptide antigens. As a result, it has been very difficult to comprehensively study the TCR repertoire or identify and track more than a few antigen-specific T cells in mice or humans. For mouse studies, this had led to a reliance on model antigens and TCR transgenes. The study of limited human clinical samples, in contrast, requires techniques that can simultaneously survey TCR phenotype and function, and TCR reactivity to many T-cell epitopes. Thanks to recent advances in single-cell and cytometry methodologies, as well as high-throughput sequencing of the TCR repertoire, we now have or will soon have the tools needed to comprehensively analyze T-cell responses in health and disease.

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Figure 1: Antigen recognition by the T-cell receptor and probing antigen specificity with peptide–MHC multimers.
Figure 2: Single-cell analysis can reveal heterogeneity in gene expression among T cells.
Figure 3: Highly multiplexed analysis of T-cell antigen specificity using mass cytometry–based combinatorial peptide–MHC tetramer staining.
Figure 4: Strategies for high-throughput single-cell analysis of TCR sequences and identification of TCR ligands.

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Authors and Affiliations

  1. Agency for Science, Technology and Research (A*STAR), Singapore Immunology Network (SIgN), Singapore

    Evan W Newell

  2. Department of Microbiology and Immunology, The Howard Hughes Medical Institute, Stanford, California, USA

    Mark M Davis

  3. Institute for Immunity, Transplantation and Infection, The Howard Hughes Medical Institute, Stanford, California, USA

    Mark M Davis

  4. The Howard Hughes Medical Institute, Stanford, California, USA

    Mark M Davis

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Newell, E., Davis, M. Beyond model antigens: high-dimensional methods for the analysis of antigen-specific T cells. Nat Biotechnol 32, 149–157 (2014). https://doi.org/10.1038/nbt.2783

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