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

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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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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