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 r...

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Bibliographic Details
Published in:Journal of autoimmunity 2015-09, Vol.63, p.13-22
Main Authors: Jenkinson, William E, McCarthy, Nicholas I, Dutton, Emma E, Cowan, Jennifer E, Parnell, Sonia M, White, Andrea J, Anderson, Graham
Format: Article
Language:English
Subjects:
Aire
Allergy and Immunology
Animals
Autoimmunity - immunology
Cell Differentiation
Cellular Microenvironment - immunology
Central tolerance
Humans
Immune Tolerance
Mice
Mice, Inbred BALB C
nTh17
T cell
Th17 Cells - immunology
Th17 Cells - metabolism
Thymic epithelium
Thymus
Thymus Gland - embryology
Thymus Gland - immunology
Thymus Gland - metabolism
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Summary: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.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2015.06.008