title: The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development.
abstract: A key role of the thymic medulla is to negatively select autoreactive CD4(+) and CD8(+) thymocytes, a process important for T cell tolerance induction. However, the involvement of the thymic medulla in other aspects of αβ T cell development, including the generation of Foxp3(+) natural regulatory T cells (nTreg cells) and the continued maturation of positively selected conventional αβ T cells, is unclear. We show that newly generated conventional CD69(+)Qa2(-) CD4 single-positive thymocytes mature to the late CD69(-)Qa2(+) stage in the absence of RelB-dependent medullary thymic epithelial cells (mTECs). Furthermore, an increasing ability to continue maturation extrathymically is observed within the CD69(+)CCR7(-/lo)CCR9(+) subset of conventional SP4 thymocytes, providing evidence for an independence from medullary support by the earliest stages after positive selection. In contrast, Foxp3(+) nTreg cell development is medullary dependent, with mTECs fostering the generation of Foxp3(-)CD25(+) nTreg cell precursors at the CD69(+)CCR7(+)CCR9(-) stage. Our results demonstrate a differential requirement for the thymic medulla in relation to CD4 conventional and Foxp3(+) thymocyte lineages, in which an intact mTEC compartment is a prerequisite for Foxp3(+) nTreg cell development through the generation of Foxp3(-)CD25(+) nTreg cell precursors.
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, England, UK.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cowan
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakamura
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Caamano
authors.forename: Peter J L
authors.initials: PJ
authors.lastname: Lane
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D054388:Receptors, CCR / Q000235:genetics / Q000276:immunology; D054400:Receptors, CCR7 / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D060168:Thymocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051858:Forkhead Transcription Factors; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054388:Receptors, CCR; D054400:Receptors, CCR7; D051841:Transcription Factor RelB; D000099192:CD69 Antigens; C119309:CC chemokine receptor 9; C515371:Ccr7 protein, mouse; C498833:Foxp3 protein, mouse; C032907:Q surface antigens; C497594:Relb protein, mouse