第 3 组先天淋巴细胞 (ILC3) 在发育中或健康的肠道中含量丰富，可在响应微生物定植时关键支持组织稳态。然而，肠道 ILC3 在慢性感染、结直肠癌或炎症性肠病 (IBD) 期间会减少，而驱动这些改变的机制仍知之甚少。在这里，我们对 IBD 患者的 ILC3 进行 RNA 测序，观察到肠道炎症期间坏死性凋亡的中央调节因子 RIPK3 显着上调。这是在小鼠中建立的模型，我们发现肠道 ILC3 表达 RIPK3，与淋巴组织诱导物 (LTi) 样 ILC3 相比，传统 (c)ILC3 表现出高 RIPK3 和低水平的促生存基因。 ILC3 特异性 RIPK3 受到肠道微生物群的促进，在肠道感染后进一步上调，并依赖于 IL-23R 和 STAT3 信号传导。然而，谱系特异性删除 RIPK3 揭示了 ILC3 存活中的多余作用，因为 caspase 8 阻断了 RIPK3 介导的坏死性凋亡，而 caspase 8 也因肠道感染而被激活。相比之下，谱系特异性删除 caspase 8 会导致健康肠道中的 cILC3 以及肠道感染期间所有 ILC3 子集的丢失，从而增加病原体负担和肠道炎症。 Caspase 8 的这一功能需要 TNF 或 TL1A 诱导的催化活性，如果同时删除 RIPK3，则该功能是可有可无的。 Caspase 8 激活和细胞死亡与 ILC3s 上的 Fas 增加有关，并且肠道感染期间 cILC3s 上调 Fas-FasL 通路，这可以抑制肠道 ILC3s 的丰度。总的来说，这些数据表明，对关键细胞因子信号的解释控制着微生物挑战后 ILC3 的存活，并且这些途径的不平衡（例如在 IBD 中或跨 ILC3 子集）会引起发炎肠道中组织保护性 ILC3 的消耗。版权所有 © 2024爱思唯尔公司出版。

Group 3 innate lymphoid cells (ILC3s) are abundant in the developing or healthy intestine to critically support tissue homeostasis in response to microbial colonization. However, intestinal ILC3s are reduced during chronic infections, colorectal cancer, or inflammatory bowel disease (IBD), and the mechanisms driving these alterations remain poorly understood. Here we employed RNA sequencing of ILC3s from IBD patients and observed a significant upregulation of RIPK3, the central regulator of necroptosis, during intestinal inflammation. This was modeled in mice where we found that intestinal ILC3s express RIPK3, with conventional (c)ILC3s exhibiting high RIPK3 and low levels of pro-survival genes relative to lymphoid tissue inducer (LTi)-like ILC3s. ILC3-specific RIPK3 is promoted by gut microbiota, further upregulated following enteric infection, and dependent upon IL-23R and STAT3 signaling. However, lineage-specific deletion of RIPK3 revealed a redundant role in ILC3 survival, due to a blockade of RIPK3-mediated necroptosis by caspase 8, which was also activated in response to enteric infection. In contrast, lineage-specific deletion of caspase 8 resulted in loss of cILC3s from the healthy intestine and all ILC3 subsets during enteric infection, which increased pathogen burdens and gut inflammation. This function of caspase 8 required catalytic activity induced by TNF or TL1A and was dispensable if RIPK3 was simultaneously deleted. Caspase 8 activation and cell death were associated with increased Fas on ILC3s, and the Fas-FasL pathway was upregulated by cILC3s during enteric infection, which could restrain the abundance of intestinal ILC3s. Collectively, these data reveal that interpretation of key cytokine signals controls ILC3 survival following microbial challenge, and that an imbalance of these pathways, such as in IBD or across ILC3 subsets, provokes depletion of tissue-protective ILC3s from the inflamed intestine.Copyright © 2024. Published by Elsevier Inc.