Department of Immunology and Genomic Medicine, Kyoto University Graduate School of Medicine, 606-8501 Kyoto, Japan.
Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, 230-0045 Yokohama, Japan.
Proc Natl Acad Sci U S A. 2020 Sep 22;117(38):23674-23683. doi: 10.1073/pnas.2010981117. Epub 2020 Sep 9.
The gut microbiome has garnered attention as an effective target to boost immunity and improve cancer immunotherapy. We found that B cell-defective (BCD) mice, such as µ-membrane targeted deletion (µMT) and activation-induced cytidine deaminase (AID) knockouts (KOs), have elevated antitumor immunity under specific pathogen-free but not germ-free conditions. Microbial dysbiosis in these BCD mice enriched the type I IFN (IFN) signature in mucosal CD8 T cells, resulting in up-regulation of the type I IFN-inducible protein stem cell antigen-1 (Sca-1). Among CD8 T cells, naïve cells predominantly circulate from the gut to the periphery, and those that had migrated from the mesenteric lymph nodes (mLNs) to the periphery had significantly higher expression of Sca-1. The gut-educated Sca-1 naïve subset is endowed with enhanced mitochondrial activity and antitumor effector potential. The heterogeneity and functional versatility of the systemic naïve CD8 T cell compartment was revealed by single-cell analysis and functional assays of CD8 T cell subpopulations. These results indicate one of the potential mechanisms through which microbial dysbiosis regulates antitumor immunity.
肠道微生物组已成为增强免疫力和改善癌症免疫治疗的有效靶点。我们发现，在特定无病原体而非无菌条件下，B 细胞缺陷（BCD）小鼠（如靶向 µ 膜的缺失（µMT）和激活诱导胞苷脱氨酶（AID）敲除（KO））具有更高的抗肿瘤免疫力。这些 BCD 小鼠中的微生物失调使粘膜 CD8 T 细胞中 I 型 IFN（IFN）特征丰富，导致 I 型 IFN 诱导蛋白干细胞抗原-1（Sca-1）上调。在 CD8 T 细胞中，幼稚细胞主要从肠道循环到外周，而从肠系膜淋巴结（mLN）迁移到外周的细胞 Sca-1 的表达显著增加。肠道教育的 Sca-1 幼稚亚群具有增强的线粒体活性和抗肿瘤效应功能。通过对 CD8 T 细胞亚群的单细胞分析和功能测定，揭示了系统幼稚 CD8 T 细胞区室的异质性和多功能性。这些结果表明了微生物失调调节抗肿瘤免疫的潜在机制之一。
