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Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance

Nature Immunology volume 11, pages 512–519 (2010)Cite this article

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Abstract

Medullary thymic epithelial cells (mTECs) serve an essential function in central tolerance by expressing peripheral-tissue antigens. These antigens may be transferred to and presented by dendritic cells (DCs). Therefore, it is unclear whether mTECs, in addition to being an antigen reservoir, also serve a mandatory function as antigen-presenting cells. Here we diminished major histocompatibility complex (MHC) class II on mTECs through transgenic expression of a 'designer' microRNA specific for the MHC class II transactivator CIITA (called 'C2TA' here). This resulted in an enlarged polyclonal CD4+ single-positive compartment and, among thymocytes specific for model antigens expressed in mTECs, enhanced selection of regulatory T cells (Treg cells) at the expense of deletion. Our data document an autonomous contribution of mTECs to both dominant and recessive mechanisms of CD4+ T cell tolerance and support an avidity model of Treg cell development versus deletion.

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Figure 1: Lower MHC class II expression through Ciita silencing in vitro.
Figure 2: Transgenic expression of the C2TA-specific synthetic miRNA in mTECs.
Figure 3: Silencing of Ciita and MHC class II genes in C2TAkd mTECs.
Figure 4: Phenotype, APC-function and promiscuous PTA expression of C2TAkd mTECs.
Figure 5: Nonredundant contribution of mTECs and hematopoietic APCs to the deletional tolerance of CD4+ T cells.
Figure 6: Rescue from clonal deletion and enhanced generation of OVA-specific Treg cells in DO11.10 × Aire-OVA × C2TAkd thymi.
Figure 7: Rescue from clonal deletion and enhanced generation of HA-specific Treg cells in TCR-HA × Aire-HA × C2TAkd thymi.
Figure 8: The C2TAkd-mediated cell-fate conversion of DO11.10 × Aire-OVA thymocytes is independent of cross-presentation by DCs.

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Acknowledgements

We thank B. Kyewski for critical reading of the manuscript; C. Federle and S. Hoeflinger for technical assistance; C. Theussl for BAC injections; M.S. Anderson (University of California, San Francisco) for Adig mice; K. Karjalainen (Nanyang Technological University) for A5 hybridoma cells; and H.S. Scott (University of Adelaide) for monoclonal antibody to Aire. Supported by the Deutsche Forschungsgemeinschaft (KL 1228/3-1 to L.K. and M.H.; SFB 455 to L.K. and M.A.; and VO 944/2-2 to D.V.) and the Austrian National Science Fund (SFB23).

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Authors and Affiliations

  1. Institute for Immunology, Ludwig-Maximilians-Universität, Munich, Germany

    Maria Hinterberger, Martin Aichinger, David Voehringer & Ludger Klein

  2. Institute for Medical Microbiology, Immunology and Hygiene, Technical University Munich, Munich, Germany

    Olivia Prazeres da Costa & Reinhard Hoffmann

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  1. Maria Hinterberger
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Contributions

M.H. generated and analyzed the C2TAkd model as well as the compound transgenic mice and bone marrow chimeras and was also essentially involved in all other experiments; M.A. did expression analyses by quantitative PCR; O.P.d.C. and R.H. did microarray experiments; D.V. provided ΔDC mice; and L.K. and M.H. designed experimental strategies and wrote the manuscript.

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Correspondence to Ludger Klein.

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Hinterberger, M., Aichinger, M., Prazeres da Costa, O. et al. Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nat Immunol 11, 512–519 (2010). https://doi.org/10.1038/ni.1874

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