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Fli1 drives the terminal differentiation of a memory precursor-like NK cell during viral infection

ABSTRACT: Natural killer (NK) cells are innate lymphocytes that possess traits of adaptive immunity, such as clonal expansion, contraction, and generation of long-lived memory cells following viral infection. However, the molecular mechanisms by which clonally expanded effector NK (NKeff) cells persist to form memory cells is not well understood. Utilizing single cell RNA sequencing, we identify two Ly49H+ NKeff cell populations following mouse cytomegalovirus (MCMV) infection defined by the cell surface protein Ly6C. Ly6C– NKeff cells displayed enhanced survival during the contraction phase in a BCL2-dependent manner. Ly6C– NKeff cells displayed distinct transcriptional and epigenetic signatures compared to Ly6C+ NKeff cells, with a core epigenetic signature shared with memory precursor (MP) CD8+ T cells enriched in ETS1 and Fli1 DNA-binding motifs. Fli1 regulated memory NK cell fate by promoting terminal maturation and decreased persistence of contracting NK cells. Our results suggest that memory NK cells, similar to memory T cells, are generated by a subset of epigenetically distinct MP cell states that preferentially survive during the contraction phase of the response to viral infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE176208 | GEO | 2022/01/12

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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Fli1 drives the terminal differentiation of a memory precursor-like NK cell during viral infection

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