Letter | Published:

Early events in the thymus affect the balance of effector and regulatory T cells

Naturevolume 444pages10731077 (2006) | Download Citation

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Abstract

In cellular immunology the critical balance between effector and regulatory mechanisms is highlighted by serious immunopathologies attributable to mutations in Foxp3, a transcription factor required for a major subset of regulatory T (Tr) cells1,2,3. Thus, many studies have focused on the developmental origin of Tr cells, with the prevailing view that they emerge in the thymus from late-stage T-cell progenitors whose T-cell receptors (TCRs) engage high affinity (agonist) ligands4,5,6. This study questions the completeness of that interpretation. Here we show that without any obvious effect on TCR-mediated selection, the normal differentiation of mouse γδ T cells into potent cytolytic and interferon-γ-secreting effector cells is switched towards an aggregate regulatory phenotype by limiting the capacity of CD4+CD8+ T-cell progenitors to influence in trans early γδ cell progenitors. Unexpectedly, we found that the propensity of early TCR-αβ+ progenitors to differentiate into Foxp3+ Tr cells is also regulated in trans by CD4+CD8+ T-cell progenitor cells, before agonist selection.

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Acknowledgements

The authors thank the Wellcome Trust for support, and W. Turnbull, E. Wise, G. Warnes, T. Tree, L. Graca, A. Aguirre, P. Pereira, D. Gibbons, S. Haque, Jian-Guo Chai, H. Brady, C. Langford, P. Ellis, J. Lewis, M. Girardi and R. Tigelaar for assistance, support and discussions. T.S. is supported by a Ph.D. scholarship from the Boehringer Ingelheim Fonds.

Author information

Affiliations

  1. Peter Gorer Department of Immunobiology, King’s College London School of Medicine, Guy’s Hospital, London, SE1 9RT, UK

    • Daniel J. Pennington
    • , Bruno Silva-Santos
    • , Tobias Silberzahn
    • , Mónica Escórcio-Correia
    •  & Adrian C. Hayday
  2. Institute of Cell and Molecular Science, The London and Barts School of Medicine and Dentistry, Queen Mary College, London, E1 2AT, UK

    • Daniel J. Pennington
  3. Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Lisboa, 1649-028, Portugal

    • Bruno Silva-Santos
  4. Molecular Haematology and Cancer Biology Unit, Camelia Botnar Laboratories, Institute of Child Health, University College, London, WC1N 1EH, UK

    • Martin J. Woodward
  5. Department of Dermatology, Yale University School of Medicine, New Haven, 15 York Street HRT 603, Connecticut, 06510, USA

    • Scott J. Roberts
  6. Institute for Animal Health, Compton Laboratory, Compton, Newbury, Berks, RG20 7NN, UK

    • Adrian L. Smith
  7. Division of Medicine, Imperial College, Hammersmith Hospital, London, Du Cane Road, W12 0HS, UK

    • P. Julian Dyson

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Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding authors

Correspondence to Daniel J. Pennington or Adrian C. Hayday.

Supplementary information

  1. Supplementary Figure 1

    FACS profiles demonstrating that splenic yδ cells from pTα-deficient mice express similar Vy chains to those from WT animals.

  2. Supplementary Figure 2

    FACS profiles demonstrating that yδ cells from TCRβ-/- and pTα-/- mice express Foxp3.

  3. Supplementary Figure 3

    Data demonstrating that ICER expression can subset DN2 thymocytes.

  4. Supplementary Figure 4

    Representation of the data obtained from transcriptional profiling of DN2 cells from WT (DN2-L and DN2-S) and pTα-/- mice demonstrating that WT DN2-S cells are more similar to pTα-/- DN2 cells than to WT DN2-L cells.

  5. Supplementary Figure 5

    A revised scheme for regulatory T cell development.

  6. Supplementary Table 1

    Table of absolute cell number of cell populations from the thymus, spleen, or small intestine (Gut) of wild type or pTα-/- mice.

  7. Supplementary Table 2

    Table showing the percentage of TCRαβ+CD4+CD8α- [CD4+ SP] thymocytes from age-matched wild type mice [WT] (n=3) and pTα-/- mice (n=5) that express TCR chains that include either Vα2, Vβ3, Vβ5.1/5.2 or Vβ8.1/8.2.

  8. Supplementary Table 3

    Table illustrating a selection of genes overexpressed in WT DN2 cells compared to pTα-/- DN2 cells

  9. Supplementary Table 4

    Primers used for semi-quantitative and Real-Time PCR.

  10. Supplementary Figure Legends

    This file contains text to accompany the above Supplementary Figures and Supplementary Tables

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https://doi.org/10.1038/nature06051

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