Antigen Recognition By Autoreactive Cd4+ Thymocytes Drives Homeostasis Of The Thymic Medulla |
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| Authors: | Magali Irla Lucia Guerri Jeanne Guenot Arnauld Sergé Olivier Lantz Adrian Liston Beat A. Imhof Ed Palmer Walter Reith |
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| Affiliation: | 1. Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.; 2. Département de Biologie des Tumeurs and Inserm U932, Institut Curie, Paris, France.; 3. Autoimmune Genetics Laboratory, VIB and University of Leuven, Leuven, Belgium.; 4. Experimental Transplantation Immunology, Department of Biomedicine, University Hospital-Basel, Basel, Switzerland.; Oklahoma Medical Research Foundation, United States of America, |
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| 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. |
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