Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
J Exp Med. 2024 Mar 4;221(3). doi: 10.1084/jem.20230124. Epub 2024 Jan 10.
Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells.
固有淋巴细胞 (ILC) 是一类具有异质性的淋巴细胞群体，能够协调早期免疫反应并维持组织内稳态。1 型固有免疫应答由自然杀伤 (NK) 细胞和 ILC1 群 (ILC1) 介导。尽管具有共同特征，但 NK 细胞和 ILC1 在各种组织微环境中存在显著差异。在这里，我们使用组织相关和循环 NK/ILC1 的 scRNA-seq 图谱，将肌醇多磷酸酶 INPP4B 鉴定为组织驻留 ILC1 和肿瘤内 NK 细胞的特征标志物。在 ILC1 和 NK 细胞中条件性缺失 Inpp4b 表明，它对于组织驻留 ILC1 的稳态是必需的，但对于稳态下的循环 NK 细胞则不是必需的。Inpp4b 缺陷细胞显示出更高的凋亡率和 AKT 等存活分子的激活减少。此外，NK/ILC1 表达 Inpp4b 对于其存在于肿瘤内环境中是必需的，而缺乏 Inpp4b 会损害抗肿瘤免疫。这些发现强调了 INPP4B 作为 ILC1 和 NK 细胞组织驻留和抗肿瘤功能的新型调节剂。
