title: Antigen recognition by autoreactive CD4⁺ thymocytes drives homeostasis of the thymic medulla.
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.
authors.affiliation: Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland. Magali.Irla@unige.ch
authors.forename: Magali
authors.initials: M
authors.lastname: Irla
authors.forename: Lucia
authors.initials: L
authors.lastname: Guerri
authors.forename: Jeanne
authors.initials: J
authors.lastname: Guenot
authors.forename: Arnauld
authors.initials: A
authors.lastname: Sergé
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Beat A
authors.initials: BA
authors.lastname: Imhof
authors.forename: Ed
authors.initials: E
authors.lastname: Palmer
authors.forename: Walter
authors.initials: W
authors.lastname: Reith
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019521:Body Patterning; D015704:CD4 Antigens / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006706:Homeostasis; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology / Q000254:growth & development* / Q000276:immunology; D046509:Tissue Culture Techniques
chemical_list: D001324:Autoantigens; D015704:CD4 Antigens; D019013:CD40 Antigens; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D023201:CD40 Ligand