title: Differential requirement for CCR4 and CCR7 during the development of innate and adaptive αβT cells in the adult thymus.
abstract: αβT cell development depends upon serial migration of thymocyte precursors through cortical and medullary microenvironments, enabling specialized stromal cells to provide important signals at specific stages of their development. Although conventional αβT cells are subject to clonal deletion in the medulla, entry into the thymus medulla also fosters αβT cell differentiation. For example, during postnatal periods, the medulla is involved in the intrathymic generation of multiple αβT cell lineages, notably the induction of Foxp3(+) regulatory T cell development and the completion of invariant NKT cell development. Although migration of conventional αβT cells to the medulla is mediated by the chemokine receptor CCR7, how other T cell subsets gain access to medullary areas during their normal development is not clear. In this study, we show that combining a panel of thymocyte maturation markers with cell surface analysis of CCR7 and CCR4 identifies distinct stages in the development of multiple αβT cell lineages in the thymus. Although Aire regulates expression of the CCR4 ligands CCL17 and CCL22, we show that CCR4 is dispensable for thymocyte migration and development in the adult thymus, demonstrating defective T cell development in Aire(-/-) mice is not because of a loss of CCR4-mediated migration. Moreover, we reveal that CCR7 controls the development of invariant NKT cells by enabling their access to IL-15 trans-presentation in the thymic medulla and influences the balance of early and late intrathymic stages of Foxp3(+) regulatory T cell development. Collectively, our data identify novel roles for CCR7 during intrathymic T cell development, highlighting its importance in enabling multiple αβT cell lineages to access the thymic medulla.
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cowan
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: McCarthy
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: White
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Andrea
authors.initials: A
authors.lastname: Bacon
authors.affiliation: Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM Unité Mixte de Recherche 1068, Centre National de la Recherche Scientifique Unité Mixte de Recherche 7258, Aix-Marseille University, UM 105, F-13009 Marseille, France; and.
authors.forename: Arnauld
authors.initials: A
authors.lastname: Serge
authors.affiliation: Centre d'Immunologie de Marseille-Luminy, INSERM Unité Mixte de Recherche 631, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Aix-Marseille University, UM 2, F-13009 Marseille, France.
authors.forename: Magali
authors.initials: M
authors.lastname: Irla
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Peter J L
authors.initials: PJ
authors.lastname: Lane
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Jenkinson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.affiliation: Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; g.anderson@bham.ac.uk.
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000276:immunology*; D019070:Cell Lineage / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis*; D054398:Receptors, CCR4 / Q000172:deficiency / Q000502:physiology*; D054400:Receptors, CCR7 / Q000172:deficiency / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C515371:Ccr7 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054398:Receptors, CCR4; D054400:Receptors, CCR7