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  • Review Article
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The many important facets of T-cell repertoire diversity

Nature Reviews Immunology volume 4, pages 123–132 (2004)Cite this article

Key Points

  • Intense investigation has elucidated the molecular mechanisms that generate the structural diversity of the T-cell receptor (TCR) repertoire. The first reliable estimates of actual TCR diversity were recently published, however, the biological impact of TCR diversity is still being investigated.

  • Potential TCR diversity, which is in the order of 1 × 1015 before thymic selection, and 1 × 1013 after thymic selection, stands in sharp contrast with the estimated actual, expressed diversity in a given organism at a given time point — 2 × 106 in mice and 2 × 107 in humans. This limit is imposed in part by the fact that there are fewer T cells in the body than there are potential TCR molecules.

  • However, the potential of ∼1 × 1013 TCRs is used, but in different organisms over time. It was shown that even genetically identical animals express highly diverse TCR repertoires, with as little as 20% overlap between them.

  • Structural TCR diversity is broadened by TCR crossreactivity — the propensity of a TCR to react with more than one peptide–MHC (pMHC) ligand. However, sharp differences exist in our estimates of TCR crossreactivity (some authors estimate that a single TCR might recognize more than 1 × 106 pMHC ligands) and in the threshold at which this crossreactivity becomes important in pathogen resistance.

  • T cells also show functional diversification (that is, the ability to mobilize distinct effector and regulatory functions) and this diversity is probably important for combating pathogens.

  • T-cell diversity contributes to immune defence in two ways: it provides an initial pool from which the best and most efficient T cells will be selected to attack the pathogen; and it provides the flexible TCR reserve should the pathogen attempt to escape by mutation.

  • Evidence from models with experimental or spontaneous restrictions in TCR diversity shows that in most models, even modest reductions in structural diversity tend to result in impaired responses to antigens and pathogens. This indicates that in most cases, TCR crossreactivity cannot compensate for the loss of structural diversity, indicating that the biological relevance of TCR crossreactivity for pathogen resistance is rather limited.

  • There is a natural reduction in TCR diversity on aging and a pathophysiological reduction in TCR diversity after infection with HIV/highly active antiretroviral therapy and after bone-marrow transplantation. These conditions represent outstanding (and clinically relevant) models to further investigate the in vivo relevance of a broad TCR repertoire and functional T-cell diversification.

  • A given combination of T-cell structural and functional diversity and T-cell precursor numbers will probably prove to be crucial for successful pathogen resistance, and TCR crossreactivity could also have a role. The challenge is to use incisive methods to uncover this balance and dissect its precise components, to achieve optimal protective responses by vaccination and immune modulation.

Abstract

In the thymus, a diverse and polymorphic T-cell repertoire is generated by random recombination of discrete T-cell receptor (TCR)-αβ gene segments. This repertoire is then shaped by intrathymic selection events to generate a peripheral T-cell pool of self-MHC restricted, non-autoaggressive T cells. It has long been postulated that some optimal level of TCR diversity allows efficient protection against pathogens. This article focuses on several recent advances that address the required diversity for the generation of an optimal immune response.

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Figure 1: Overview of the interaction between T-cell receptor (TCR) and peptide–MHC (pMHC).
Figure 2: T-cell diversity.
Figure 3: Overview of the concepts of affinity and avidity.

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Acknowledgements

We wish to thank D. Parker and S. Murray (OHSU) for critical perusing of the manuscript. Our work is supported by the United States Public Health Service and the National Institutes of Health.

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  1. Department of Molecular Microbiology and Immunology and the Oregon National Primate Research Center, Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, 97006, Oregon, USA

    Janko Nikolich-Žugich, Mark K. Slifka & Ilhem Messaoudi

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  1. Janko Nikolich-Žugich
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Correspondence to Janko Nikolich-Žugich.

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Glossary

STRUCTURAL DIVERSITY

The availability of T cells that express a wide array of T-cell receptors (TCRs), specific for the same epitope, that differ from each other in the TCR segments used, primary and/or tertiary structure.

FUNCTIONAL DIVERSITY

The ability of activated T cells, all specific for a single epitope, to have one or more distinct effector functions, such as proliferation, cytokine secretion (different cytokines), cytolysis, migration and homing.

STRUCTURAL AVIDITY

Is determined by the direct binding affinities of multiple cell-bound T-cell receptor molecules for peptide–MHC (pMHC); most commonly measured by staining with pMHC multimers.

FUNCTIONAL AVIDITY

Relates the binding avidity of an antigen-specific T cell to a measurable biological function (proliferation, cytokine production or cytolytic activity) at different doses of peptide antigen.

TCR IMMUNODOMINANCE

The preferential recruitment of a T-cell population that expresses restricted T-cell receptor (TCR) elements (Vα, Vβ) in response to a given epitope, mainly determined by the structural characteristics and avidity of the responding T-cell population.

IMMUNODOMINANT EPITOPES

One or a few epitopes that a pathogen-specific T-cell response focuses on. Immunodominance is mainly determined by antigen processing and presentation, the abundance of the antigenic protein, the ability of the epitope to bind the given MHC molecule and the availability of a responding T-cell population.

IMMUNODOMINANCE

A phenomenon that arises from T-cell economy in response to antigen. Out of all possible combinations, only a few T cells will respond to a few epitopes of the pathogen, so as to produce focused, effective responses.

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Nikolich-Žugich, J., Slifka, M. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nat Rev Immunol 4, 123–132 (2004). https://doi.org/10.1038/nri1292

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