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Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells

Nature Immunology volume 8, pages 351–358 (2007)Cite this article

Abstract

The parameters specifying whether autoreactive CD4+ thymocytes are deleted (recessive tolerance) or differentiate into regulatory T cells (dominant tolerance) remain unresolved. Dendritic cells directly delete thymocytes, partly through cross-presentation of peripheral antigens 'promiscuously' expressed in medullary thymic epithelial cells (mTECs) positive for the autoimmune regulator Aire. It is unclear if and how mTECs themselves act as antigen-presenting cells during tolerance induction. Here we found that an absence of major histocompatibility class II molecules on mTECs resulted in fewer polyclonal regulatory T cells. Furthermore, targeting of a model antigen to Aire+ mTECs led to the generation of specific regulatory T cells independently of antigen transfer to dendritic cells. Thus, 'routing' of mTEC-derived self antigens may determine whether specific thymocytes are deleted or enter the regulatory T cell lineage.

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Figure 1: Selection of polyclonal Foxp3+CD25+ Treg cells by MHC class II expressed exclusively on thymic epithelium.
Figure 2: In situ detection of Foxp3+ cells in MHC class II–positive or MHC class II–negative medullary 'islands' in mixed RTOCs.
Figure 3: Medulla-specific expression of HA-GFP with bacterial artificial chromosome transgenesis.
Figure 4: Generation of Foxp3+CD25+ Treg cells in AIRE-HA × TCR-HA mice.
Figure 5: Expression of HA in AIRE-HA thymic epithelium but not expression in hematopoietic cells recapitulates the phenotype of AIRE-HA × TCR-HA mice.
Figure 6: Display of HA(107–119) by isolated mTECs and DCs but not by cTECs from AIRE-HA thymi.
Figure 7: Efficient generation of Foxp3+CD25+ Treg cells independently of cross-presentation by hematopoietic cells.

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Acknowledgements

We thank M.S. Anderson, B. Kyewski and J. Derbinski for comments on the manuscript. K. Karjalainen (Nanyung Technological University) provided the A5 hybridoma; A. Rudensky (University of Washington) provided Foxp3-specific polyclonal rabbit serum; R. Boyd (Monash Medical School) provided MTS10 supernatant; and B. Kyewski (German Cancer Research Center) provided biotinylated antibody to MHC class II. Supported by Boehringer Ingelheim (Research Institute of Molecular Pathology), the European Union (Euro-Thymaide FP6 Integrated Project; LSHB-CT-2003-503410) and the Austrian National Science Fund (Z58-B01 and Sonderforschungsbereich F023).

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Author notes

  1. Louise M D'Cruz & Elisabeth H Vollmann

    Present address: Present addresses: Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA (L.M.D.) and The CBR Institute for Biomedical Research, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (E.H.V.).,

Authors and Affiliations

  1. Research Institute of Molecular Pathology, 1030, Vienna, Austria

    Katharina Aschenbrenner, Louise M D'Cruz, Elisabeth H Vollmann, Maria Hinterberger, Jan Emmerich & Ludger Klein

  2. Department of Clinical and Biological Sciences, Center for Biomedicine, University of Basel, Basel, CH-4051, Switzerland

    Lee Kim Swee & Antonius Rolink

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Contributions

K.A. generated and analyzed AIRE-HA × TCR-HA mice; L.M.D. did the RTOC experiments; E.H.V. generated and analyzed AIRE-OVA × DO11.10 mice together with J.E.; M.H. contributed to the generation and analysis of nude chimeras; L.K.S. and A.R. generated and analyzed CD11c-HA × TCR-HA mice (Supplementary Fig. 3); and L.K. prepared the manuscript.

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Correspondence to Ludger Klein.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Generation of mixed RTOC, outline of the experimental procedure. (PDF 594 kb)

Supplementary Fig. 2

A distinct population of TCR-HA+CD25+Foxp3+ cells among peripheral CD4+ T cells in AIRE-HA × TCR-HA mice. (PDF 963 kb)

Supplementary Fig. 3

Targeting of HA to DCs in CD11c-HA × TCR-HA mice results in efficient intra-thymic deletion of TCR-HA+ cells. (PDF 76 kb)

Supplementary Fig. 4

Targeting of OVA to mTECs leads to generation of OVA–specific CD25+Foxp3+ Treg cells. (PDF 107 kb)

Supplementary Fig. 5

Presentation of HA(107-119) by DCs resulting from capture of mTEC-derived antigen. (PDF 57 kb)

Supplementary Methods (PDF 79 kb)

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Aschenbrenner, K., D'Cruz, L., Vollmann, E. et al. Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire+ medullary thymic epithelial cells. Nat Immunol 8, 351–358 (2007). https://doi.org/10.1038/ni1444

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