Sequential phases in the development of Aire-expressing medullary thymic epithelial cells involve distinct cellular input.

Abstract:

: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.

journal_name

Eur J Immunol

authors

White AJ,Withers DR,Parnell SM,Scott HS,Finke D,Lane PJ,Jenkinson EJ,Anderson G

doi

10.1002/eji.200738052

subject

Has Abstract

pub_date

2008-04-01 00:00:00

pages

942-7

issue

4

eissn

0014-2980

issn

1521-4141

journal_volume

38

pub_type

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