Jennifer A. Foltz, Jennifer Tran, Pamela Wong, Changxu Fan, Evelyn Schmidt, Bryan Fisk, Michelle Becker-Hapak, David A. Russler-Germain, Jeanette Johnson, Nancy D. Marin, Celia C. Cubitt, Patrick Pence, Joseph Rueve, Sushanth Pureti, Kimberly Hwang, Feng Gao, Alice Y. Zhou, Mark Foster, Timothy Schappe, Lynne Marsala, Melissa M. Berrien-Elliott, Amanda F. Cashen, Jeffrey J. Bednarski, Elana Fertig, Obi L. Griffith, Malachi Griffith, Ting Wang, Allegra A. Petti, Todd A. Fehniger
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引用次数: 0
摘要
用白细胞介素-12(IL-12)、IL-15 和 IL-18 等细胞因子激活自然杀伤(NK)细胞可诱导其分化为记忆样(ML)NK 细胞;然而,其潜在的表观遗传和转录机制尚不清楚。通过结合ATAC-seq、CITE-seq和功能分析,我们发现IL-12/15/18激活会导致两种主要的人类NK命运:重编程为富集记忆样(eML)NK细胞或激发为效应传统NK(effcNK)细胞。研究还发现了两个转录离散的 eML NK 细胞亚群:eML-1 和 eML-2,它们分别主要来自 CD56 明亮或 CD56 模糊的成熟 NK 细胞亚群。此外,这些eML亚群在将IL-12/15/18激活的NK细胞转移到癌症患者体内数周后显现出来。我们的研究结果表明,用IL-12/15/18激活NK细胞会产生以前未曾认识到的多种细胞命运,并确定了加强NK疗法的新策略。
Cytokines drive the formation of memory-like NK cell subsets via epigenetic rewiring and transcriptional regulation
Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56bright or CD56dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.
期刊介绍:
Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.