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Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla

Guerri, Lucia
Lantz, Olivier
Liston, Adrian
Palmer, Ed
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Published in PloS one. 2012, vol. 7, no. 12, e52591
Abstract The thymic medulla is dedicated for purging the T-cell receptor (TCR) repertoire of self-reactive specificities. Medullary thymic epithelial cells (mTECs) play a pivotal role in this process because they express numerous peripheral tissue-restricted self-antigens. Although it is well known that medulla formation depends on the development of single-positive (SP) thymocytes, the mechanisms underlying this requirement are incompletely understood. We demonstrate here that conventional SP CD4⁺ thymocytes bearing autoreactive TCRs drive a homeostatic process that fine-tunes medullary plasticity in adult mice by governing the expansion and patterning of the medulla. This process exhibits strict dependence on TCR-reactivity with self-antigens expressed by mTECs, as well as engagement of the CD28-CD80/CD86 costimulatory axis. These interactions induce the expression of lymphotoxin α in autoreactive CD4⁺ thymocytes and RANK in mTECs. Lymphotoxin in turn drives mTEC development in synergy with RANKL and CD40L. Our results show that Ag-dependent interactions between autoreactive CD4⁺ thymocytes and mTECs fine-tune homeostasis of the medulla by completing the signaling axes implicated in mTEC expansion and medullary organization.
Keywords AnimalsAntigens, CD4/metabolismAntigens, CD40/metabolismAutoantigens/immunologyBody PatterningCD40 Ligand/metabolismCell ProliferationEpithelial Cells/metabolism/physiologyFemaleGene ExpressionHomeostasisLymphotoxin beta Receptor/metabolismLymphotoxin-alpha/genetics/metabolismMaleMiceMice, Inbred C57BLMice, KnockoutReceptor Activator of Nuclear Factor-kappa B/metabolismSignal TransductionThymocytes/immunology/metabolism/physiologyThymus Gland/cytology/growth & development/immunologyTissue Culture Techniques
PMID: 23300712
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Research groups Groupe Reith Walter (pathologie et immunologie) (282)
Molécules d'adhésion et processus de migration cellulaire (167)
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IRLA, Magali et al. Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla. In: PloS one, 2012, vol. 7, n° 12, p. e52591. doi: 10.1371/journal.pone.0052591 https://archive-ouverte.unige.ch/unige:29182

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Deposited on : 2013-08-12

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