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  • Review Article
  • Published:

Tracking T cells with tetramers: new tales from new tools

Nature Reviews Immunology volume 2, pages 263–272 (2002)Cite this article

Key Points

  • Tetrameric peptide–MHC-class-I complexes (tetramers) allow antigen-specific T cells to be tracked in time and space, as well as a detailed analysis of their surface phenotype.

  • Tetramers are best used in parallel with functional assays.

  • Very large, focused expansions of T-cell populations are seen early after infection.

  • The very large T-cell populations expand rapidly and can also contract rapidly.

  • After the acute phase of infection, substantial populations of antigen-specific T cells might persist long term, but the size of the population varies depending on the pathogen.

  • Various T-cell phenotypes exist following acute disease, which vary between infections and between individuals.

  • Antigen-specific T cells are found readily outside lymphoid organs during and after acute disease.

  • Tetramer-positive cells are antigen specific, but not uniformly antigen responsive.

  • Tumour-specific CD8+ T-cell responses do arise spontaneously, but differ from antiviral responses in magnitude and, potentially, duration.

  • Spontaneous tumour-specific CD8+ T-cell responses might often be 'too little, too late'.

  • The function of tumour-specific CD8+ T cells might vary, similar to virus-specific CD8+ T cells.

  • Tetramers have highlighted the overlap between tumour immunity and autoimmunity.

  • Tumour vaccination trials benefit from the use of tetramers.

  • Tetramers for CD4+ T cells and natural killer T cells exist but have yet to make the same impact as MHC class I tetramers. However, tetramers of non-classical MHC class I molecules (for example, HLA-E) have been important in identifying new pathways of natural-killer-cell regulation.

  • The future is bright for tetramer studies, but it is important to remember that they can only be interpreted in the context of the entire immune response.

Abstract

To understand the success or failure of immune responses against pathogens or tumours requires the direct measurement of specific lymphocytes. Recently, there has been an explosion of data in this field through the use of several new tools for measuring the number and function of T cells. This has allowed immunologists who study human disease and mouse models of infection and cancer to readily track specific T cells — in both time and space. Although there are common patterns, over time, each host–pathogen relationship seems to develop unique characteristics, as reflected in the quality of the T-cell response.

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Figure 1: Patterns of tetramer staining over time.
Figure 2: Simplified phenotype of tetramer-positive cells in human infectious disease.
Figure 3: An example of CD8+ T-cell distribution associated with viral infection (vesicular stomatitis virus).
Figure 4: Dose-response curve for pathogen-specific T-cell populations.

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Acknowledgements

This work was sponsored by the Wellcome Trust, the European Union, the British Medical Association (Roscoe Fellowship), Cancer Research UK and the Medical Research Council (UK). We thank C. Norbury for his critical reading of the manuscript and T. Klenerman for assistance in its preparation.

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Authors and Affiliations

  1. Nuffield Department of Medicine, University of Oxford, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK

    Paul Klenerman

  2. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK

    Vincenzo Cerundolo & P. Rod Dunbar

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  1. Paul Klenerman
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  2. Vincenzo Cerundolo
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  3. P. Rod Dunbar
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Correspondence to Paul Klenerman.

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Glossary

ELISPOT ASSAY

An antibody-capture-based method for enumerating specific T cells (CD4 or CD8) that can secrete a cytokine (usually interferon-γ). After development with a colour reagent, each single spot represents one antigen-specific T cell.

BYSTANDER ACTIVATION

The activation of T cells without encounter with their specific antigen — that is, without triggering by their T-cell receptor.

INTRACELLULAR CYTOKINE STAIN

(ICS). Analysis of the ability of T cells to produce a cytokine in response to a specific stimulus. In this assay, the usual cytokine-secretion pathway is paralyzed, and intracellular accumulation of the cytokine is monitored by antibody staining and fluorescence-activated cell sorting analysis.

EXHAUSTION

An 'operational' definition that refers to the loss of antigen-specific T-cell responses in vivo after prolonged or repetitive stimulation with antigen. This has been best observed in a model of infection with lymphocytic choriomeningitis virus Docile strain, for which the exact mechanism is still not understood.

STUNNING

A term for T cells in a state of 'pre-exhaustion'; they can be detected by tetramers but seem to be refractory to further stimulation.

IGNORANCE

Failure to initiate a T-cell response by lack of encounter with antigen. Might be due to compartmentalization of antigen or suboptimal antigen presentation.

CROSS-PRIMING

Initiation of a CD8+ T-cell response against an antigen that is not present within antigen-presenting cells. The antigen must be taken up by APCs and then re-routed to the MHC class I presentation pathway.

NKT CELL

A T cell that bears a specific αβ T-cell receptor that is able to recognize lipid–CD1d complexes. NKT cells express a set of natural-killer-cell markers, notably CD161 in humans and NK1.1 in some mouse strains.

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Klenerman, P., Cerundolo, V. & Dunbar, P. Tracking T cells with tetramers: new tales from new tools. Nat Rev Immunol 2, 263–272 (2002). https://doi.org/10.1038/nri777

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