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

Nature volume 444, pages 1073–1077 (2006)Cite this article

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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Figure 1: Activated splenic γδ cells from Tcrb-/- mice express activated DETC-specific genes and display regulatory potential in vitro.
Figure 2: γδ cells from Tcrb-/- and Ptcra-/- mice express Foxp3.
Figure 3: Ptcra -/- CD4 + TCR-αβ hi thymocytes and splenocytes are enriched for Foxp3 + regulatory cells.
Figure 4: Trans -conditioning regulates the differential capacity of early thymic progenitors to develop into T cells with regulatory characteristics.

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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.

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

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Supplementary information

Supplementary Figure 1

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

Supplementary Figure 2

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

Supplementary Figure 3

Data demonstrating that ICER expression can subset DN2 thymocytes.

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.

Supplementary Figure 5

A revised scheme for regulatory T cell development.

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.

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.

Supplementary Table 3

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

Supplementary Table 4

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

Supplementary Figure Legends

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

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Pennington, D., Silva-Santos, B., Silberzahn, T. et al. Early events in the thymus affect the balance of effector and regulatory T cells. Nature 444, 1073–1077 (2006). https://doi.org/10.1038/nature06051

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