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Tissue determinants of human NK cell development, function and residence

ABSTRACT: Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigated how tissue localization regulates the development and function of human Natural Killer (NK) cells, an innate lymphocyte important for anti-viral and tumor immunity. Integrating high dimensional analysis of NK cells from blood, lymphoid organs and mucosal tissue sites from 48 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation and function across age and genetic diversity. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen and lungs, exhibiting shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity prevail in lymph nodes and intestines, exhibiting tissue resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue resident populations, while mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites.

ORGANISM(S): Homo sapiens

PROVIDER: GSE133383 | GEO | 2020/02/03

REPOSITORIES: GEO

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Project description:Cervical cancer (CC) is one of the most common malignancy in women worldwide. It is characterized by a natural continuous phenomenon, that is, it is in the initial stage of HPV infection, progresses to intraepithelial neoplasia, and then develops into invasion and metastasis. Determining the complexity of tumor microenvironment (TME) can deepen our understanding of lesion progression and provide novel therapeutic strategies for CC. We performed the single-cell RNA sequencing on the normal cervix, intraepithelial neoplasia, primary tumor and metastatic lymph node tissues to describe the composition, lineage, and functional status of immune cells and mesenchymal cells at different stages of CC progression. A total of 59913 single cells were obtained and divided into 9 cellular clusters, including immune cells (T/NK cells, macrophages, B cells, plasma cells, mast cells and neutrophils) and mesenchymal cells (endothelial cells, smooth muscle cells and fibroblasts). Our results showed that there were distinct cell subpopulations in different stages of CC. High-stage intraepithelial neoplasia (HSIL) tissue exhibited a low, recently activated TME, and it was characterized by high infiltration of tissue-resident CD8 T cell, effector NK cells, Treg, DC1, pDC, and M1-like macrophages. Tumor tissue displayed high enrichment of exhausted CD8 T cells, resident NK cells and M2-like macrophages, suggesting immunosuppressive TME. Metastatic lymph node consisted of naive T cell, central memory T cell, circling NK cells, cytotoxic CD8+ T cells and effector memory CD8 T cells, suggesting an early activated phase of immune response. This study is the first to delineate the transcriptome profile of immune cells during CC progression using single-cell RNA sequencing. Our results indicated that HSIL exhibited a low, recently activated TME, tumor displayed immunosuppressive statue, and metastatic lymph node showed early activated phase of immune response. Our study enhanced the understanding of dynamic change of TME during CC progression and has implications for the development of novel treatments to inhibit the initiation and progression of CC.

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Tissue determinants of human NK cell development, function and residence

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