Highlights d Semi-supervised learning improves doublet classification in single-cell RNA sequencing d Combining our method with experimental approaches further improves accuracy
The immune system comprises a complex network of specialized cells that protects against infection, eliminates cancerous cells, and regulates tissue repair, thus serving a critical role in homeostasis, health span, and life span. The subterranean-dwelling naked mole-rat (NM-R; Heterocephalus glaber) exhibits prolonged life span relative to its body size, is unusually cancer resistant, and manifests few physiological or molecular changes with advancing age. We therefore hypothesized that the immune system of NM-Rs evolved unique features that confer enhanced cancer immunosurveillance and prevent the age-associated decline in homeostasis. Using single-cell RNA-sequencing (scRNA-seq) we mapped the immune system of the NM-R and compared it to that of the short-lived, cancer-prone mouse. In contrast to the mouse, we find that the NM-R immune system is characterized by a high myeloid-to-lymphoid cell ratio that includes a novel, lipopolysaccharide (LPS)-responsive, granulocyte cell subset. Surprisingly, we also find that NM-Rs lack canonical natural killer (NK) cells. Our comparative genomics analyses support this finding, showing that the NM-R genome lacks an expanded gene family that controls NK cell function in several other species. Furthermore, we reconstructed the evolutionary history that likely led to this genomic state. The NM-R thus challenges our current understanding of mammalian immunity, favoring an atypical, myeloid-biased mode of innate immunosurveillance, which may contribute to its remarkable health span.
Using single-cell transcriptional profiling we mapped the immune system of the naked mole-rat (Heterocephalus glaber), a small but long-lived and cancer-resistant subterranean rodent. Both splenic and circulating immune cells were examined in healthy young animals and following an infection-mimicking lipopolysaccharide challenge. Our study revealed that the naked mole-rat immune system is characterized by a high myeloid to lymphoid cell ratio that includes a novel, lipopolysaccharide responsive, granulocyte cell subset not found in the mouse. Conversely, we find that naked mole-rats do not have a cell subset that corresponds to natural killer cells as defined in other well-characterized mammalian species. Supporting this finding, we show that the naked mole-rat genome has not expanded any of the gene families encoding diverse natural killer cell receptors, which are the genomic hallmarks of species in which natural killer cells have been described. These unusual features suggest an atypical mode of immunosurveillance and a greater reliance on myeloid-biased innate immunity. 0
Cellular senescence involves a stable cell cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell surface proteome to alter how tumor cells sense environmental factors, as exemplified by Type II interferon (IFN-y). Compared to proliferating cells, senescent cells upregulate the IFN-y receptor, become hypersensitized to microenvironmental IFN-y, and more robustly induce the antigen presenting machinery—-effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFN-y sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals, and imply that each process is required for their effective immune surveillance.
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