美国康奈尔大学Gregory F. Sonnenberg团队近期取得重要工作进展，他们研究提出，表达CTLA-4的ILC3抑制白细胞介素-23（IL-23）介导的炎症。相关研究成果2024年6月12日在线发表于《自然》杂志上。

据介绍，白细胞介素23（IL-23）是慢性炎症性疾病的主要介质和治疗靶点，在稳态或急性感染后也能引起肠道组织保护。然而，形成这些有益与病理结果的机制仍知之甚少。

为了解决这一知识空白，研究人员对肠道中所有表达IL-23受体的细胞及其对IL-23的急性反应进行了单细胞RNA测序，揭示了T细胞和第3组先天淋巴细胞（ILC3）的优势。出研究人员在ILC3上发现了免疫调节检查点分子细胞毒性T淋巴细胞相关抗原-4（CTLA-4）的有效上调。该途径被肠道微生物和IL-23以FOXO1-和STAT3依赖的方式激活。ILC3缺乏CTLA-4的小鼠表现出调节性T细胞减少、炎症性T细胞升高和更严重的肠道炎症。IL-23对CTLA-4⁺ ILC3的诱导对于减少共刺激分子和增加PD-L1在肠髓系细胞上的生物利用度是必要且足够的。最后，人ILC3上调CTLA-4以响应IL-23或肠道炎症，并与炎症性肠病的免疫调节相关。

总之，这一结果揭示了ILC3内在的CTLA-4是抑制IL-23病理结果的重要检查点，表明这些淋巴细胞的破坏（发生在炎症性肠病中）会导致慢性炎症。

附：英文原文

Title: CTLA-4-expressing ILC3s restrain interleukin-23-mediated inflammation

Author: Ahmed, Anees, Joseph, Ann M., Zhou, Jordan, Horn, Veronika, Uddin, Jazib, Lyu, Mengze, Goc, Jeremy, Sockolow, Robbyn E., Wing, James B., Vivier, Eric, Sakaguchi, Shimon, Sonnenberg, Gregory F.

Issue&Volume: 2024-06-12

Abstract: Interleukin (IL-)23 is a major mediator and therapeutic target in chronic inflammatory diseases that also elicits tissue protection in the intestine at homeostasis or following acute infection1,2,3,4. However, the mechanisms that shape these beneficial versus pathological outcomes remain poorly understood. To address this gap in knowledge, we performed single-cell RNA sequencing on all IL-23 receptor-expressing cells in the intestine and their acute response to IL-23, revealing a dominance of T cells and group 3 innate lymphoid cells (ILC3s). Unexpectedly, we identified potent upregulation of the immunoregulatory checkpoint molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on ILC3s. This pathway was activated by gut microbes and IL-23 in a FOXO1- and STAT3-dependent manner. Mice lacking CTLA-4 on ILC3s exhibited reduced regulatory T cells, elevated inflammatory T cells and more-severe intestinal inflammation. IL-23 induction of CTLA-4+ ILC3s was necessary and sufficient to reduce co-stimulatory molecules and increase PD-L1 bioavailability on intestinal myeloid cells. Finally, human ILC3s upregulated CTLA-4 in response to IL-23 or gut inflammation and correlated with immunoregulation in inflammatory bowel disease. These results reveal ILC3-intrinsic CTLA-4 as an essential checkpoint that restrains the pathological outcomes of IL-23, suggesting that disruption of these lymphocytes, which occurs in inflammatory bowel disease5,6,7, contributes to chronic inflammation.

DOI: 10.1038/s41586-024-07537-3

Source: https://www.nature.com/articles/s41586-024-07537-3