Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here, we showed that tonsillar ILCs expressing CD45RA lacked proliferative activity, indicative of cellular quiescence. CD62L distinguished two subsets of CD45RA + ILCs. CD45RA + CD62L + ILCs (CD62L + ILCs) resembled circulating naïve ILCs because they lacked the transcriptional, metabolic, epigenetic, and cytokine production signatures of differentiated ILCs. CD45RA + CD62L − ILCs (CD62L − ILCs) were epigenetically similar to CD62L + ILCs but showed a transcriptional, metabolic, and cytokine production signature that was more akin to differentiated ILCs. CD62L + and CD62L − ILCs contained uni- and multipotent precursors of ILC1s/NK cells and ILC3s. Differentiation of CD62L + and CD62L − ILCs led to metabolic reprogramming including up-regulation of genes associated with glycolysis, which was needed for their effector functions after differentiation. CD62L − ILCs with preferential differentiation capacity toward IL-22–producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease. These data suggested distinct differentiation potential of CD62L + and CD62L − ILCs between tissue microenvironments and identified that manipulation of these cells is a possible approach to restore tissue-immune homeostasis.

中文翻译：

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CD45RA + CD62L - 人体组织中的 ILC 代表了产生分化 ILC 的静止局部储存库

先天淋巴细胞 (ILC) 是高度可塑性且主要是黏膜组织驻留细胞，根据微环境有助于体内平衡和炎症。幼稚样 ILC 的发现表明 ILC 分化过程类似于幼稚 T 细胞分化。描绘组织中 ILC 分化的机制对于了解健康和疾病中的 ILC 生物学至关重要。在这里，我们发现表达 CD45RA 的扁桃体 ILC 缺乏增殖活性，表明细胞处于静止状态。CD62L 区分了 CD45RA 的两个子集+ILC。CD45RA+CD62L+ILC（CD62L+ILC) 类似于循环中的初始 ILC，因为它们缺乏分化 ILC 的转录、代谢、表观遗传和细胞因子产生特征。CD45RA+CD62L-ILC（CD62L-ILC）在表观遗传学上与 CD62L 相似+ILCs 但显示出更类似于分化的 ILCs 的转录、代谢和细胞因子产生特征。CD62L+和 CD62L-ILCs 包含 ILC1s/NK 细胞和 ILC3s 的单能和多能前体。CD62L的分化+和 CD62L-ILC 导致代谢重编程，包括上调与糖酵解相关的基因，这是它们分化后的效应器功能所必需的。CD62L-在炎症性肠病患者的炎症黏膜中积累的 ILC 对产生 IL-22 的 ILC3 具有优先分化能力。这些数据表明 CD62L 具有明显的分化潜力+和 CD62L-组织微环境之间的 ILC，并确定对这些细胞的操作是恢复组织免疫稳态的一种可能方法。