title: Rank signaling links the development of invariant γδ T cell progenitors and Aire(+) medullary epithelium.
abstract: The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire. Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation.
authors.affiliation: MRC Centre for Immune Regulation, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Roberts
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: White
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.forename: Gleb
authors.initials: G
authors.lastname: Turchinovich
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: David R
authors.initials: DR
authors.lastname: Withers
authors.forename: Fiona M
authors.initials: FM
authors.lastname: McConnell
authors.forename: Guillaume E
authors.initials: GE
authors.lastname: Desanti
authors.forename: Cecile
authors.initials: C
authors.lastname: Benezech
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paolino
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Anna Katharina
authors.initials: AK
authors.lastname: Simon
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nitta
authors.forename: Izumi
authors.initials: I
authors.lastname: Ohigashi
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Takahama
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Caamano
authors.forename: Adrian C
authors.initials: AC
authors.lastname: Hayday
authors.forename: Peter J L
authors.initials: PJ
authors.lastname: Lane
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D060833:Cellular Microenvironment; D004847:Epithelial Cells / Q000276:immunology; D005260:Female; D005333:Fetus / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology*; D011247:Pregnancy; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000096927:AIRE Protein
chemical_list: D053246:Receptor Activator of Nuclear Factor-kappa B; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014157:Transcription Factors; D000096927:AIRE Protein; C505687:Tnfrsf11a protein, mouse