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
The thymic medulla plays an essential, non-redundant role in the generation of central T-cell tolerance
The detection of natural Th17 cells is potentially confounded by the presence of multiple Tcell and innate-like lymphoid cells that possess the shared capacity to produce IL-17, including gdT-cell, invariant natural killer T (iNKT) and group 3 innate lymphoid cell (ILC) subsets [26]
NTh17 detected within adult murine thymus demonstrated an activated/memory phenotype, being CCR6þCD44HI, and in contrast to the majority of thymic iNKT, natural T helper 17 (nTh17) were characterized by an absence of NK1.1 expression (Fig. 1B and Supplementary Fig. 1)
Summary
The thymic medulla plays an essential, non-redundant role in the generation of central T-cell tolerance. In addition to the elimination of autoreactive T-cell clones, operating through the concerted action of both medullary thymic cells and dendritic cells [2], medullary microenvironments play a pivotal role in the generation of intrathymically effector primed ‘natural’ abT-cell subsets including natural regulatory T-cells (nTreg) and invariant natural killer cells (iNKT) [3e5]. In addition to nTreg and iNKT, recent studies have presented evidence revealing the existence of natural IL-17 secreting abT-cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
