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

• 成果类型: Article
• 署名作者: 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.
• 署名单位: Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of Osaka; University of Osaka; University of Osaka; Aix-Marseille Universite; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Aix-Marseille Universite; Assistance Publique-Hopitaux de Marseille; Kyoto University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4391
• DOI: 10.1038/s41586-024-07537-3
• 发表日期: 2024-06-27
• 页码: 976-+
• 关键词: innate lymphoid-cells; genome-wide association; intestinal homeostasis; maintenance therapy; mice reveal; il-23; microbiota; induction; ustekinumab; regulator

摘要

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 infection(1-4). 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 disease(5-7), contributes to chronic inflammation.