Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Leibniz Institute of Immunotherapy (LIT), Chair for Immunology, University of Regensburg, Regensburg, Germany.
Nat Commun. 2022 Apr 19;13(1):2027. doi: 10.1038/s41467-022-29734-2.
Innate lymphoid cells (ILCs) govern immune cell homeostasis in the intestine and protect the host against microbial pathogens. Various cell-intrinsic pathways have been identified that determine ILC development and differentiation. However, the cellular components that regulate ILC sustenance and function in the intestinal lamina propria are less known. Using single-cell transcriptomic analysis of lamina propria fibroblasts, we identify fibroblastic reticular cells (FRCs) that underpin cryptopatches (CPs) and isolated lymphoid follicles (ILFs). Genetic ablation of lymphotoxin-β receptor expression in Ccl19-expressing FRCs blocks the maturation of CPs into mature ILFs. Interactome analysis shows the major niche factors and processes underlying FRC-ILC crosstalk. In vivo validation confirms that a sustained lymphotoxin-driven feedforward loop of FRC activation including IL-7 generation is critical for the maintenance of functional ILC populations. In sum, our study indicates critical fibroblastic niches within the intestinal lamina propria that control ILC homeostasis and functionality and thereby secure protective gut immunity.
固有淋巴细胞 (ILCs) 调控肠道中免疫细胞的稳态，并保护宿主免受微生物病原体的侵害。现已确定了多种决定 ILC 发育和分化的细胞内途径。然而，调节肠道固有层中 ILC 维持和功能的细胞成分知之甚少。通过对固有层成纤维细胞的单细胞转录组分析，我们鉴定了支撑隐窝（CPs）和孤立淋巴滤泡（ILFs）的纤维网状细胞（FRCs）。在 Ccl19 表达的 FRC 中敲除淋巴毒素-β 受体的表达会阻止 CPs 成熟为成熟的 ILFs。相互作用组分析显示了 FRC-ILC 串扰的主要生态位因子和过程。体内验证证实，FRC 激活的持续淋巴毒素驱动的正反馈回路，包括 IL-7 的产生，对于维持功能性 ILC 群体至关重要。总之，我们的研究表明，肠道固有层内存在关键的成纤维细胞生态位，它们控制 ILC 的稳态和功能，从而确保了保护性的肠道免疫。
