Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
Cell. 2021 Dec 22;184(26):6281-6298.e23. doi: 10.1016/j.cell.2021.11.018. Epub 2021 Dec 6.
While intestinal Th17 cells are critical for maintaining tissue homeostasis, recent studies have implicated their roles in the development of extra-intestinal autoimmune diseases including multiple sclerosis. However, the mechanisms by which tissue Th17 cells mediate these dichotomous functions remain unknown. Here, we characterized the heterogeneity, plasticity, and migratory phenotypes of tissue Th17 cells in vivo by combined fate mapping with profiling of the transcriptomes and TCR clonotypes of over 84,000 Th17 cells at homeostasis and during CNS autoimmune inflammation. Inter- and intra-organ single-cell analyses revealed a homeostatic, stem-like TCF1 IL-17 SLAMF6 population that traffics to the intestine where it is maintained by the microbiota, providing a ready reservoir for the IL-23-driven generation of encephalitogenic GM-CSF IFN-γ CXCR6 T cells. Our study defines a direct in vivo relationship between IL-17 non-pathogenic and GM-CSF and IFN-γ pathogenic Th17 populations and provides a mechanism by which homeostatic intestinal Th17 cells direct extra-intestinal autoimmune disease.
虽然肠道 Th17 细胞对于维持组织内稳态至关重要，但最近的研究表明它们在包括多发性硬化症在内的多种肠外自身免疫性疾病的发展中起作用。然而，组织 Th17 细胞介导这些双重功能的机制尚不清楚。在这里，我们通过对超过 84000 个 Th17 细胞在稳态和中枢神经系统自身免疫炎症期间的转录组和 TCR 克隆型的分析，结合命运图谱，对组织 Th17 细胞的异质性、可塑性和迁移表型进行了表征。器官间和器官内的单细胞分析揭示了一种具有组织内稳态、干细胞样 TCF1IL-17SLAMF6 特性的群体，它可以迁移到肠道，在那里它被微生物群维持，为 IL-23 驱动的致脑炎性 GM-CSFIFN-γCXCR6T 细胞的产生提供了一个现成的储备库。我们的研究定义了 IL-17 非致病性和 GM-CSF 和 IFN-γ 致病性 Th17 群体之间的直接体内关系，并提供了一种组织内稳态肠道 Th17 细胞指导肠外自身免疫性疾病的机制。
