Natural Th17 cells are critically regulated by functional medullary thymic microenvironments. (September 2015)

• Record Type: Journal Article
• Authors: Jenkinson, William E.; McCarthy, Nicholas I.; Dutton, Emma E.; Cowan, Jennifer E.; Parnell, Sonia M.; White, Andrea J.; Anderson, Graham
• Is Part Of: Journal of autoimmunity. Volume 63(2015)
• Page Start: 13
• Page End: 22
• Publication Date: 2015-09
• Subjects: Thymus -- Central tolerance -- Thymic epithelium -- nTh17 -- T cell -- Aire; Aire autoimmune regulator -- dGuO 2-deoxyguanosine -- FTOC fetal thymic organ culture -- iNKT invariant natural killer T -- iNOS inducible nitric oxide synthase -- mTEC medullary TEC -- nTh17 natural T helper 17 -- nTreg natural T regulatory -- SP4 single positive CD4+8− thymocyte -- TEC thymic epithelial cell; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.06.008
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: Thymic stromal MHC class II regulates intrathymic nTh17. RelB-dependent medullary thymic epithelium is critical for nTh17 development. Aire and B7 family costimulatory ligands regulate thymic nTh17. Medullary thymic epithelium constitutively expresses iNOS. iNOS is not essential for regulation of thymic nTh17.