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  • Review Article
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Structural determinants of T-cell receptor bias in immunity

Nature Reviews Immunology volume 6, pages 883–894 (2006)Cite this article

Key Points

  • Antigen-specific T-cell responses are often characterized by the preferred use of specific T-cell receptors (which is known as TCR bias).

  • The bias in TCR usage can be categorized based on the diversity in a specific T-cell population.

  • There is evidence that after infection, the selection of a diverse TCR repertoire correlates with increased levels of immune protection.

  • Consistent selection by different individuals of the same antigen-specific TCR sequences is an example of a 'public' TCR repertoire. A 'private' TCR repertoire occurs when there is little or no overlap in TCR sequences between individuals.

  • TCR bias can be influenced by many factors, such as thymic selection and antigen-driven selection, which can narrow the available T-cell repertoire over time.

  • The topology of a given peptide–MHC complex is an important factor in determining the level of TCR bias in a responding T-cell population.

  • The most extreme TCR bias (type 3) is associated with peptide–MHC complexes that present unique challenges for recognition.

Abstract

Antigen-specific T-cell responses induced by infection, transplantation, autoimmunity or hypersensitivity are characterized by cells expressing biased profiles of T-cell receptors (TCRs) that are selected from a diverse, naive repertoire. Here, we review the evidence for these TCR biases, focusing on crystallographic analysis of the structural constraints that determine the binding of a TCR to its ligand and the persistence of certain TCRs in an immune repertoire. We discuss the ways in which diversity in a selected TCR repertoire can contribute to protective immunity and the implications of this for vaccine design and immunotherapy.

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Figure 1: Generation of T-cell receptor (TCR) diversity by somatic recombination of TCR gene segments.
Figure 2: 'Footprint' of T-cell receptor contacts with cognate peptide–MHC complexes.
Figure 3: Types of T-cell receptor bias in antigen-specific T-cell repertoires.
Figure 4: An example of a peptide–MHC complex selecting a type 3 TCR bias.
Figure 5: The topology of peptide–MHC class I complexes can influence T-cell receptor (TCR) repertoire diversity.

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Acknowledgements

We thank N. La Gruta, K. Kedzierska, S. Burrows and S. Perlman for critical review of the manuscript. Support was provided by a Burnet Fellowship of the National Health and Medical Research Council (NHMRC) of Australia (P.C.D.), an NHMRC R.D. Wright Fellowship (S.J.T.) and an Australian Research Council (ARC) Professorial and Federation Fellowship (J.R.). Further funding came from the Government of Victoria (Australia), the ARC, the NHMRC, the Juvenile Diabetes Research Foundation, a United States Public Health Service grant and the American Lebanese Syrian Associated Charities at St Jude Children's Research Hospital (Memphis, Tennessee, USA).

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Authors and Affiliations

  1. The Department of Microbiology and Immunology, The University of Melbourne, Parkville, 3010, Victoria, Australia

    Stephen J. Turner, Peter C. Doherty & James McCluskey

  2. Department of Biochemistry and Molecular Biology, The Protein Crystallography Unit, Monash University, Clayton, 3800, Victoria, Australia

    Jamie Rossjohn

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  1. Stephen J. Turner
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Correspondence to Stephen J. Turner.

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Glossary

Positive selection

The process in the thymus that selects thymocytes expressing T-cell receptors (TCRs) that can interact weakly with self-MHC molecules. This weak interaction generates differentiation and survival signals in these lymphocytes, the TCRs of which later recognize foreign peptides bound to self-MHC. Positive selection establishes the MHC-restricted T-cell repertoire.

Negative selection

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self-peptide bound to self-MHC molecules undergo apoptosis in response to the signalling generated by high-affinity binding.

TCR bias

The selection of antigen-specific T cells that show preferential usage of particular T-cell receptor (TCR) variable region gene-segment combinations in response to antigen. TCR bias can be grouped into type 1, type 2 or type 3 TCR bias.

T-cell fitness

The ability of a given naive T-cell precursor to cross a threshold of TCR-mediated signals that enable selection into the antigen-specific immune repertoire.

Best-fit TCR

A T-cell receptor (TCR) that shows marked structural complementarity with its cognate peptide–MHC antigen, resulting in optimal, high-avidity interactions. Conversely, a less-fit TCR does not show good structural complementarity with cognate peptide–MHC complexes, resulting in suboptimal, low-avidity interactions.

Peptide–MHC tetramer

Biotinylated monomeric MHC molecules are folded with a specific peptide in the binding groove and tetramerized with a fluorescently labelled streptavidin molecule. Tetramers will bind to T cells that express T-cell receptors specific for the cognate peptide.

Reverse genetics

Genetic analysis that proceeds from genotype to phenotype through gene-manipulation techniques. For example, a reverse-genetics strategy enables the generation of infectious influenza A viruses from cloned plasmid cDNAs. The plasmid-based system enables mutations to be introduced into the coding regions of specific virus gene segments using recombinant PCR.

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Turner, S., Doherty, P., McCluskey, J. et al. Structural determinants of T-cell receptor bias in immunity. Nat Rev Immunol 6, 883–894 (2006). https://doi.org/10.1038/nri1977

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