Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development,Nature

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Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development
Nature ( IF 50.5 ) Pub Date : 2018-07-01 , DOI: 10.1038/s41586-018-0345-2
Corey N Miller _{1,

2} , Irina Proekt _{1,

2} , Jakob von Moltke _{2,

3,

4,

5} , Kristen L Wells ₆ , Aparna R Rajpurkar ₆ , Haiguang Wang ₇ , Kristin Rattay _{8,

9} , Imran S Khan _{1,

2,

10} , Todd C Metzger _{1,

2,

11} , Joshua L Pollack _{2,

12} , Adam C Fries ₁₃ , Wint W Lwin _{1,

2} , Eric J Wigton ₃ , Audrey V Parent _{1,

2} , Bruno Kyewski ₈ , David J Erle ₂ , Kristin A Hogquist ₇ , Lars M Steinmetz ₆ , Richard M Locksley _{2,

3,

4} , Mark S Anderson _{1,

2,

3}

Affiliation

Diabetes Center, University of California, San Francisco, San Francisco, CA, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA.
Department of Immunology, University of Washington, Seattle, WA, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Division of Immunology, Harvard Medical School, Boston, MA, USA.
Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.
Bristol-Myers Squibb, Sunnyvale, CA, USA.
Pionyr Immunotherapeutics, San Francisco, CA, USA.
Biological Imaging Development Center and Department of Pathology, University of California, San Francisco, CA, USA.

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.A comprehensive analysis of the thymic medulla identifies a tuft-cell-like thymic epithelial cell population that is necessary for shaping thymic function.

中文翻译：

胸腺簇细胞促进富含 IL-4 的髓质并塑造胸腺细胞发育

胸腺负责产生多样化且具有自我耐受性的 T 细胞库1。尽管胸腺髓质主要由发育和成熟的 AIRE+ 上皮细胞组成，但最近的证据表明，胸腺髓质上皮细胞之间的异质性比以前认为的要大得多2。在这里，我们详细描述了一个上皮亚群，该亚群与粘膜屏障处发现的外周簇状细胞非常相似3。与外周细胞类似，胸腺簇细胞表达经典味觉传导途径和 IL-25。然而，它们在与角化聚集体的空间关联、呈递抗原的能力以及表达多种味觉受体方面是独特的。一些胸腺簇细胞会经历 Aire 表达阶段，并依赖于已知的 AIRE 结合伴侣 HIPK2 来进行发育。值得注意的是，味觉化学感应蛋白 TRPM5 是其胸腺功能所必需的，通过该蛋白支持胸腺不变自然杀伤 T 细胞的发育和极化，并发挥作用建立富含 2 型细胞因子 IL-4 的髓质微环境。这些发现表明，存在一个区室化的髓质环境，其中较小且高度特化的上皮亚群的分化在塑造胸腺功能方面具有非冗余的作用。对胸腺髓质的全面分析确定了簇细胞样胸腺上皮细胞群这是塑造胸腺功能所必需的。

更新日期：2018-07-01

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