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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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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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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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)
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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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DOI: https://doi.org/10.1038/ni1444
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