1. Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla.
- Author
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Irla M, Guerri L, Guenot J, Sergé A, Lantz O, Liston A, Imhof BA, Palmer E, and Reith W
- Subjects
- Animals, Body Patterning, CD40 Antigens metabolism, CD40 Ligand metabolism, Cell Proliferation, Epithelial Cells metabolism, Epithelial Cells physiology, Female, Gene Expression, Lymphotoxin beta Receptor metabolism, Lymphotoxin-alpha genetics, Lymphotoxin-alpha metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor Activator of Nuclear Factor-kappa B metabolism, Signal Transduction, Thymocytes immunology, Thymocytes metabolism, Thymus Gland cytology, Thymus Gland immunology, Tissue Culture Techniques, Autoantigens immunology, CD4 Antigens metabolism, Homeostasis, Thymocytes physiology, Thymus Gland growth & development
- 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.
- Published
- 2012
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