Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input.
Intrathymic deletion of immature thymocytes that express self-reactive TCR specificities is essential in the generation of self tolerance. Medullary thymic epithelial cells (mTEC) expressing the transcriptional regulator Aire play a key role in this process by regulating expression of tissue-restricted antigens to ensure tolerance to peripheral tissues. Here, we have analysed the cellular and molecular requirements for the initial appearance of Aire+ mTEC in the embryonic thymus, in addition to their persistence in the adult thymus. Analysis of thymic ontogeny shows that the emergence of embryonic Aire+ mTEC occurs prior to the appearance of mature thymocytes, and depends upon lymphoid tissue inducer cells expressing retinoic acid receptor-related orphan receptor gamma. In the adult thymus, we show that Aire+ mTEC develop in the absence of thymocyte positive and negative selection and CD40 signalling, but are present at reduced frequency. Collectively these data support a model where the initial differentiation of Aire+ mTEC involves receptor activator of NF-kappaB (RANK)-RANKL interactions with lymphoid tissue inducer cells, with subsequent mTEC turnover and/or survival involving CD40-mediated signalling following interactions with mature CD4+ thymocytes that express CD40L.
White
Andrea J
AJ
MRC Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham Medical School, Birmingham, UK.
Withers
David R
DR
Parnell
Sonia M
SM
Scott
Hamish S
HS
Finke
Daniela
D
Lane
Peter J L
PJ
Jenkinson
Eric J
EJ
Anderson
Graham
G
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000096927:AIRE Protein
D019013:CD40 Antigens; D023201:CD40 Ligand; D014157:Transcription Factors; D000096927:AIRE Protein