Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; Berlin Institute of Health (BIH), Anna-Louisa-Karsch Strasse 2, 10117 Berlin, Germany; Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum (DRFZ), an institute of the Leibniz Association, 10117 Berlin, Germany.
Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.
Immunity. 2020 Nov 17;53(5):1015-1032.e8. doi: 10.1016/j.immuni.2020.10.012.
Solitary intestinal lymphoid tissues such as cryptopatches (CPs) and isolated lymphoid follicles (ILFs) constitute steady-state activation hubs containing group 3 innate lymphoid cells (ILC3) that continuously produce interleukin (IL)-22. The outer surface of CPs and ILFs is demarcated by a poorly characterized population of CD11c cells. Using genome-wide single-cell transcriptional profiling of intestinal mononuclear phagocytes and multidimensional flow cytometry, we found that CP- and ILF-associated CD11c cells were a transcriptionally distinct subset of intestinal cDCs, which we term CIA-DCs. CIA-DCs required programming by CP- and ILF-resident CCR6 ILC3 via lymphotoxin-β receptor signaling in cDCs. CIA-DCs differentially expressed genes associated with immunoregulation and were the major cellular source of IL-22 binding protein (IL-22BP) at steady state. Mice lacking CIA-DC-derived IL-22BP exhibited diminished expression of epithelial lipid transporters, reduced lipid resorption, and changes in body fat homeostasis. Our findings provide insight into the design principles of an immunoregulatory checkpoint controlling nutrient absorption.
孤立的肠道淋巴组织，如隐窝（CPs）和孤立淋巴滤泡（ILFs），构成了稳态激活中心，其中含有持续产生白细胞介素（IL）-22 的第三组先天淋巴样细胞（ILC3）。CPs 和 ILFs 的外表面由一群特征不明显的 CD11c 细胞划定。通过对肠道单核吞噬细胞的全基因组单细胞转录谱分析和多维流式细胞术，我们发现 CP 和 ILF 相关的 CD11c 细胞是肠道 cDC 中具有转录差异的子集，我们将其称为 CIA-DC。CIA-DC 需要通过 cDC 中的淋巴毒素-β 受体信号由 CP 和 ILF 驻留的 CCR6 ILC3 编程。CIA-DC 差异表达与免疫调节相关的基因，并在稳态时是 IL-22 结合蛋白（IL-22BP）的主要细胞来源。缺乏 CIA-DC 衍生的 IL-22BP 的小鼠表现出上皮脂质转运体表达减少、脂质吸收减少以及体脂肪稳态改变。我们的研究结果为控制营养吸收的免疫调节检查点的设计原则提供了深入了解。
