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Autoantigen-specific interactions with CD4+ thymocytes control mature medullary thymic epithelial cell cellularity

Gill, Jason
Nitta, Takeshi
Hikosaka, Yu
Williams, Ifor R.
Hubert, François-Xavier
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Published in Immunity. 2008, vol. 29, no. 3, p. 451-63
Abstract Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.
Keywords AnimalsAntigens, CD40/immunology/metabolismAutoantigens/immunologyCD4-Positive T-Lymphocytes/cytology/immunology/metabolismCD40 Ligand/immunology/metabolismEpithelial Cells/cytology/immunology/metabolismHumansMiceMice, KnockoutNuclear Proteins/immunology/metabolismSelf ToleranceThymus Gland/cytology/immunology/metabolismTrans-Activators/immunology/metabolismTranscription Factors/immunology/metabolism
Stable URL https://archive-ouverte.unige.ch/unige:1443
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PMID: 18799151
Research groups Groupe Reith Walter (pathologie et immunologie) (282)
Pathologie et immunologie (906)

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Deposited on : 2009-04-28

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