Exploring the tolerogenic function of medullary thymic epithelial cells using tissue-specific knockdown in transgenic mice

• Applicant: Professor Dr. Ludger Klein
• Subject Area: Immunology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 153724361

• Final Report Year: 2014

Final Report Abstract

Based upon the discovery of promiscuous gene expression (PGE) in mTECs and of the autoimmune regulator (Aire) gene, it has become an accepted paradigm that central T cell tolerance covers a much wider spectrum of the “immunological-self” than previously anticipated. Antigens expressed by medullary thymic epithelial cells (mTECs) may be transferred to and presented by dendritic cells. Therefore, it is unclear whether mTECs, besides being an ‘antigen reservoir’, also serve a mandatory function as antigen presenting cells. In the present proposal, we reduced major histocompatibility complex class II on mTECs through transgenic expression of a C2TA-specific ‘designer miRNA’. 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) 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 development versus deletion.

Publications

• (2010) Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance. Nature Immunology, 11 (6): 512 - 519
  Hinterberger M., Aichinger M., Prazeres da Costa O., Voehringer D., Hoffmann R. and Klein L.
  
• (2011) Autonomous versus dendritic cell dependent contributions of medullary thymic epithelial cells to central tolerance Trends in Immunology, 32(5): 188-193
  Klein L., Hinterberger M., von Rohrscheidt J. and Aichinger M.
  
• (2011) B7 / CD28 in central tolerance: costimulation promotes maturation of regulatory T cell precursors and prevents their clonal deletion. Frontiers in Immunology 2:30
  Hinterberger M., Wirnsberger G. and Klein L.
  (See online at https://doi.org/10.3389/fimmu.2011.00030)
• (2011) Probing gene function in medullary thymic epithelial cells. European Journal of Cell Biology, 91:24-30
  Aichinger M., Hinterberger M. and Klein L.
  
• (2011) Regulatory T-cell differentiation versus clonal deletion of autoreactive thymocytes. Immunology and Cell Biology, 89 (1): 45-53
  Wirnsberger G., Hinterberger M. and Klein L.