Natural Th17 cells are critically regulated by functional medullary thymic microenvironments.
Natural Th17 cells are critically regulated by functional medullary thymic microenvironments.
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DOI：
10.1016/j.jaut.2015.06.008
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发表时间：
2015-09
影响因子：
12.8
通讯作者：
Anderson G
中科院分区：
文献类型：
--
作者：
Jenkinson WE;McCarthy NI;Dutton EE;Cowan JE;Parnell SM;White AJ;Anderson G
胸腺髓质对中枢耐受性的执行至关重要。除了自身反应性t细胞的缺失，胸腺髓质支持与耐受性机制相关的异质天然αβ t细胞的成熟。天然il -17分泌CD4+αβ t细胞（nTh17）代表最近描述的成熟的天然αβ t细胞，并在胸腺内进行功能启动。尽管提出可能影响保护性或病理性炎症反应，但调节nTh17发育平衡的胸腺内机制尚不清楚。在这里，我们比较了胸腺中不同天然αβ t细胞的发育。我们发现胸腺基质MHC II类表达和relb依赖性胸腺髓样上皮细胞（mTEC），包括Aire+ mTEC，是nTh17发育的必要条件。nTh17对icos配体和CD80/86共刺激均有部分、非冗余的要求，而对胸腺上皮细胞表达CD80/86则有可有可无的作用。虽然mTEC组成性地表达诱导型一氧化氮合酶（iNOS），这是常规Th17分化的关键负调节因子，但iNOS并不是限制胸腺nTh17所必需的。这些发现强调了胸腺髓质在新的天然αβ t细胞亚群的差异调节中的关键作用，并揭示了胸腺髓质对t细胞驱动的自身免疫和炎症的额外调节。胸腺基质MHC II类调控胸腺内nTh17。relb依赖性胸腺髓质上皮对nTh17的发育至关重要。Aire和B7家族共刺激配体调节胸腺nTh17。髓样胸腺上皮组成性表达iNOS。iNOS对胸腺nTh17的调节不是必需的。
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. 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.