title: Natural Th17 cells are critically regulated by functional medullary thymic microenvironments.
abstract: The thymic medulla is critical for the enforcement of central tolerance. In addition to deletion of auto-reactive T-cells, the thymic medulla supports the maturation of heterogeneous natural αβT-cells linked to tolerance mechanisms. Natural IL-17-secreting CD4(+)αβT-cells (nTh17) represent recently described natural αβT-cells that mature and undergo functional priming intrathymically. Despite a proposed potential to impact upon either protective or pathological inflammatory responses, the intrathymic mechanisms regulating the balance of nTh17 development are unclear. Here we compare the development of distinct natural αβT-cells in the thymus. We reveal that thymic stromal MHC class II expression and RelB-dependent medullary thymic epithelial cells (mTEC), including Aire(+) mTEC, are an essential requirement for nTh17 development. nTh17 demonstrate a partial, non-redundant requirement for both ICOS-ligand and CD80/86 costimulation, with a dispensable role for CD80/86 expression by thymic epithelial cells. Although mTEC constitutively expressed inducible nitric oxide synthase (iNOS), a critical negative regulator of conventional Th17 differentiation, iNOS was not essential to constrain thymic nTh17. These findings highlight the critical role of the thymic medulla in the differential regulation of novel natural αβT-cell subsets, and reveal additional layers of thymic medullary regulation of T-cell driven autoimmunity and inflammation.
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK. Electronic address: w.e.jenkinson@bham.ac.uk.
authors.forename: William E
authors.initials: WE
authors.lastname: Jenkinson
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: McCarthy
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Dutton
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Cowan
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Parnell
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: White
authors.affiliation: MRC Centre for Immune Regulation, Institute for Biomedical Research, Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Anderson
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D002454:Cell Differentiation; D060833:Cellular Microenvironment / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism*; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000378:metabolism*
keywords: Aire; Central tolerance; T cell; Thymic epithelium; Thymus; nTh17