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Journal article

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

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  • 2013-01-10
Published in:
  • PloS one. - 2012
Animals
Autoantigens
Body Patterning
CD4 Antigens
CD40 Antigens
CD40 Ligand
Cell Proliferation
Epithelial Cells
Female
Gene Expression
Homeostasis
Lymphotoxin beta Receptor
Lymphotoxin-alpha
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Receptor Activator of Nuclear Factor-kappa B
Signal Transduction
Thymocytes
Thymus Gland
Tissue Culture Techniques
English 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.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/221799
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